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2000
Volume 25, Issue 16
  • ISSN: 1568-0266
  • E-ISSN: 1873-4294

Abstract

Numerous studies suggest that common genetic and epigenetic factors such as p53, histone deacetylase (HDAC), brain-derived neurotrophic factor (BDNF), the (Ataxia Telangiectasia mutated) ATM gene, cyclin-dependent kinase 5 (CDK5), glycogen synthase kinase 3 (GSK3) and altered expression of microRNA (miRNA) play a crucial role in cancer and neurodegeneration. As there is growing evidence that epigenetic aberrations in cancer and neurological diseases lead to complex pathophysiological changes, the simultaneous targeting of epigenetic and other related pathways by dual-target inhibitors may contribute to the discovery of more effective and personalized therapeutic options. Computer-Aided Drug Design (CADD) provides comprehensive bioinformatic, chemoinformatic, and chemometric approaches for the design of novel chemotypes of epigenetic dual-target inhibitors, enabling efficient discovery of new drug candidates for innovative treatments of these multifactorial diseases. The detailed anticancer mechanisms by which the epigenetic dual-target inhibitors alter metastatic and tumorigenic properties, influence the tumor microenvironment, or regulate the immune response are also presented and discussed in the review. To improve our understanding of the pathogenesis of cancer and neurodegeneration, this review discusses novel therapeutic agents targeting different molecular mechanisms involved in these multifactorial diseases.

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References

  1. QureshiI.A. MehlerM.F. Understanding neurological disease mechanisms in the era of epigenetics.JAMA Neurol.201370670371010.1001/jamaneurol.2013.1443 23571666
     [Google Scholar]
  2. QureshiI.A. MehlerM.F. Epigenetic mechanisms underlying the pathogenesis of neurogenetic diseases.Neurotherapeutics201411470872010.1007/s13311‑014‑0302‑1 25261112
     [Google Scholar]
  3. PtakC. PetronisA. Epigenetics and complex disease: From etiology to new therapeutics.Annu. Rev. Pharmacol. Toxicol.200848125727610.1146/annurev.pharmtox.48.113006.094731 17883328
     [Google Scholar]
  4. Tateishi-KarimataH. SugimotoN. Roles of non-canonical structures of nucleic acids in cancer and neurodegenerative diseases.Nucleic Acids Res.202149147839785510.1093/nar/gkab580 34244785
     [Google Scholar]
  5. VarelaL. Garcia-RenduelesM.E.R. Oncogenic pathways in neurodegenerative diseases.Int. J. Mol. Sci.2022236322310.3390/ijms23063223 35328644
     [Google Scholar]
  6. JakovcevskiM. AkbarianS. Epigenetic mechanisms in neurological disease.Nat. Med.20121881194120410.1038/nm.2828 22869198
     [Google Scholar]
  7. WethF.R. HoggarthG.B. WethA.F. PatersonE. WhiteM.P.J. TanS.T. PengL. GrayC. Unlocking hidden potential: Advancements, approaches, and obstacles in repurposing drugs for cancer therapy.Br. J. Cancer2024130570371510.1038/s41416‑023‑02502‑9 38012383
     [Google Scholar]
  8. LardenoijeR. IatrouA. KenisG. KompotisK. SteinbuschH.W.M. MastroeniD. ColemanP. LemereC.A. HofP.R. van den HoveD.L.A. RuttenB.P.F. The epigenetics of aging and neurodegeneration.Prog. Neurobiol.2015131216410.1016/j.pneurobio.2015.05.002 26072273
     [Google Scholar]
  9. Landgrave-GómezJ. Mercado-GómezO. Guevara-GuzmánR. Epigenetic mechanisms in neurological and neurodegenerative diseases.Front. Cell. Neurosci.201595810.3389/fncel.2015.00058 25774124
     [Google Scholar]
  10. HwangJ.Y. AromolaranK.A. ZukinR.S. The emerging field of epigenetics in neurodegeneration and neuroprotection.Nat. Rev. Neurosci.201718634736110.1038/nrn.2017.46 28515491
     [Google Scholar]
  11. MareiH.E. AlthaniA. AfifiN. HasanA. CaceciT. PozzoliG. MorrioneA. GiordanoA. CenciarelliC. p53 signaling in cancer progression and therapy.Cancer Cell Int.202121170310.1186/s12935‑021‑02396‑8 34952583
     [Google Scholar]
  12. TalebiM. TalebiM. KakouriE. FarkhondehT. Pourbagher-ShahriA.M. TarantilisP.A. SamarghandianS. Tantalizing role of p53 molecular pathways and its coherent medications in neurodegenerative diseases.Int. J. Biol. Macromol.20211729310310.1016/j.ijbiomac.2021.01.042 33440210
     [Google Scholar]
  13. WestA.C. JohnstoneR.W. New and emerging HDAC inhibitors for cancer treatment.J. Clin. Invest.20141241303910.1172/JCI69738 24382387
     [Google Scholar]
  14. RodriguesD.A. PinheiroP.S.M. SagrilloF.S. BolognesiM.L. FragaC.A.M. Histone deacetylases as targets for the treatment of neurodegenerative disorders: Challenges and future opportunities.Med. Res. Rev.20204062177221110.1002/med.21701 32588916
     [Google Scholar]
  15. AutryA.E. MonteggiaL.M. Brain-derived neurotrophic factor and neuropsychiatric disorders.Pharmacol. Rev.201264223825810.1124/pr.111.005108 22407616
     [Google Scholar]
  16. KhannaK.K. Cancer risk and the ATM gene: A continuing debate.J. Natl. Cancer Inst.2000921079580210.1093/jnci/92.10.795 10814674
     [Google Scholar]
  17. LeeJ.H. PaullT.T. Cellular functions of the protein kinase ATM and their relevance to human disease.Nat. Rev. Mol. Cell Biol.2021221279681410.1038/s41580‑021‑00394‑2 34429537
     [Google Scholar]
  18. MapelliM. MassimilianoL. CrovaceC. SeeligerM.A. TsaiL.H. MeijerL. MusacchioA. Mechanism of CDK5/p25 binding by CDK inhibitors.J. Med. Chem.200548367167910.1021/jm049323m 15689152
     [Google Scholar]
  19. ŁukasikP. ZałuskiM. GutowskaI. Cyclin-dependent kinases (CDK) and their role in diseases development–review.Int. J. Mol. Sci.2021226293510.3390/ijms22062935 33805800
     [Google Scholar]
  20. ThapaR. GuptaG. BhatA.A. AlmalkiW.H. AlzareaS.I. KazmiI. SaleemS. KhanR. AltwaijryN. DurejaH. SinghS.K. DuaK. A review of glycogen synthase kinase-3 (GSK3) inhibitors for cancers therapies.Int. J. Biol. Macromol.2023253Pt 712737510.1016/j.ijbiomac.2023.127375 37839597
     [Google Scholar]
  21. PhukanS. BabuV.S. KannojiA. HariharanR. BalajiV.N. GSK3β: Role in therapeutic landscape and development of modulators.Br. J. Pharmacol.2010160111910.1111/j.1476‑5381.2010.00661.x 20331603
     [Google Scholar]
  22. LiZ. RanaT.M. Therapeutic targeting of microRNAs: Current status and future challenges.Nat. Rev. Drug Discov.201413862263810.1038/nrd4359 25011539
     [Google Scholar]
  23. SinghT. YadavS. Role of microRNAs in neurodegeneration induced by environmental neurotoxicants and aging.Ageing Res. Rev.20206010106810.1016/j.arr.2020.101068 32283224
     [Google Scholar]
  24. YeeA.J. BensingerW.I. SupkoJ.G. VoorheesP.M. BerdejaJ.G. RichardsonP.G. LibbyE.N. WallaceE.E. BirrerN.E. BurkeJ.N. TamangD.L. YangM. JonesS.S. WheelerC.A. MarkelewiczR.J. RajeN.S. Ricolinostat plus lenalidomide, and dexamethasone in relapsed or refractory multiple myeloma: A multicentre phase 1b trial.Lancet Oncol.201617111569157810.1016/S1470‑2045(16)30375‑8 27646843
     [Google Scholar]
  25. GuoH. ZengD. ZhangH. BellT. YaoJ. LiuY. HuangS. LiC.J. LorenceE. ZhouS. GongT. JiangC. AhmedM. YaoY. NomieK.J. ZhangL. WangM. Dual inhibition of PI3K signaling and histone deacetylation halts proliferation and induces lethality in mantle cell lymphoma.Oncogene201938111802181410.1038/s41388‑018‑0550‑3 30361685
     [Google Scholar]
  26. GallowayT.J. WirthL.J. ColevasA.D. GilbertJ. BaumanJ.E. SabaN.F. RabenD. MehraR. MaA.W. AtoyanR. WangJ. BurtnessB. JimenoA. A phase I study of CUDC-101, a multitarget inhibitor of HDACs, EGFR, and HER2, in combination with chemoradiation in patients with head and neck squamous cell carcinoma.Clin. Cancer Res.20152171566157310.1158/1078‑0432.CCR‑14‑2820 25573383
     [Google Scholar]
  27. SenderowiczA.M. Small-molecule cyclin-dependent kinase modulators.Oncogene200322426609662010.1038/sj.onc.1206954 14528286
     [Google Scholar]
  28. NishikawaS. IwakumaT. Drugs targeting p53 mutations with FDA approval and in clinical trials.Cancers (Basel)202315242910.3390/cancers15020429 36672377
     [Google Scholar]
  29. NagaharaA.H. TuszynskiM.H. Potential therapeutic uses of BDNF in neurological and psychiatric disorders.Nat. Rev. Drug Discov.201110320921910.1038/nrd3366 21358740
     [Google Scholar]
  30. JinM.H. OhD.Y. ATM in DNA repair in cancer.Pharmacol. Ther.201920310739110.1016/j.pharmthera.2019.07.002 31299316
     [Google Scholar]
  31. WaqarS.N. RobinsonC. OlszanskiA.J. SpiraA. HackmasterM. LucasL. SpontonL. JinH. HeringU. CronierD. GrinbergM. Seithel-KeuthA. Diaz-PadillaI. BerlinJ. Phase I trial of ATM inhibitor M3541 in combination with palliative radiotherapy in patients with solid tumors.Invest. New Drugs202240359660510.1007/s10637‑022‑01216‑8 35150356
     [Google Scholar]
  32. TolosaE. LitvanI. HöglingerG.U. BurnD. LeesA. AndrésM.V. Gómez-CarrilloB. LeónT. del SerT. Ven GerpenJ. A phase 2 trial of the GSK‐3 inhibitor tideglusib in progressive supranuclear palsy.Mov. Disord.201429447047810.1002/mds.25824 24532007
     [Google Scholar]
  33. del SerT. SteinwachsK.C. GertzH.J. AndrésM.V. Gómez-CarrilloB. MedinaM. VericatJ.A. RedondoP. FleetD. LeónT. Treatment of alzheimer’s disease with the GSK-3 inhibitor tideglusib: A pilot study.J. Alzheimers Dis.201233120521510.3233/JAD‑2012‑120805 22936007
     [Google Scholar]
  34. SaiyedA.N. VasavadaA.R. JoharS.R.K. Recent trends in miRNA therapeutics and the application of plant miRNA for prevention and treatment of human diseases.Future J. Pharm. Sci.2022812410.1186/s43094‑022‑00413‑9 35382490
     [Google Scholar]
  35. GaoY. ZhangH. LirussiF. GarridoC. YeX.Y. XieT. Dual inhibitors of histone deacetylases and other cancer-related targets: A pharmacological perspective.Biochem. Pharmacol.202018211422410.1016/j.bcp.2020.114224 32956642
     [Google Scholar]
  36. ParkS.Y. KimJ.S. A short guide to histone deacetylases including recent progress on class II enzymes.Exp. Mol. Med.202052220421210.1038/s12276‑020‑0382‑4 32071378
     [Google Scholar]
  37. LiG. TianY. ZhuW.G. The roles of histone deacetylases and their inhibitors in cancer therapy.Front. Cell Dev. Biol.2020857694610.3389/fcell.2020.576946 33117804
     [Google Scholar]
  38. ShuklaS. TekwaniB.L. Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation.Front. Pharmacol.20201153710.3389/fphar.2020.00537 32390854
     [Google Scholar]
  39. LoPrestiP. HDAC6 in diseases of cognition and of neurons.Cells20201011210.3390/cells10010012 33374719
     [Google Scholar]
  40. BardaiF.H. PriceV. ZaaymanM. WangL. D’MelloS.R. Histone deacetylase-1 (HDAC1) is a molecular switch between neuronal survival and death.J. Biol. Chem.201228742354443545310.1074/jbc.M112.394544 22918830
     [Google Scholar]
  41. BardaiF.H. D’MelloS.R. Selective toxicity by HDAC3 in neurons: Regulation by Akt and GSK3β.J. Neurosci.20113151746175110.1523/JNEUROSCI.5704‑10.2011 21289184
     [Google Scholar]
  42. GuptaR. AmbastaR.K. KumarP. Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders.Life Sci.202024311727810.1016/j.lfs.2020.117278 31926248
     [Google Scholar]
  43. SausvilleE.A. Complexities in the development of cyclin-dependent kinase inhibitor drugs.Trends Mol. Med.200284Suppl.S32S3710.1016/S1471‑4914(02)02308‑0 11927285
     [Google Scholar]
  44. ShapiroG.I. Cyclin-dependent kinase pathways as targets for cancer treatment.J. Clin. Oncol.200624111770178310.1200/JCO.2005.03.7689 16603719
     [Google Scholar]
  45. HarperJ.W. ElledgeS.J. The role of Cdk7 in CAK function, a retro-retrospective.Genes Dev.199812328528910.1101/gad.12.3.285 9450924
     [Google Scholar]
  46. MorganD.O. Principles of CDK regulation.Nature1995374651813113410.1038/374131a0 7877684
     [Google Scholar]
  47. SherrC.J. RobertsJ.M. Inhibitors of mammalian G1 cyclin-dependent kinases.Genes Dev.19959101149116310.1101/gad.9.10.1149 7758941
     [Google Scholar]
  48. MeinhartA. KamenskiT. HoeppnerS. BaumliS. CramerP. A structural perspective of CTD function.Genes Dev.200519121401141510.1101/gad.1318105 15964991
     [Google Scholar]
  49. SongM. QiangY. ZhaoX. SongF. Cyclin-dependent Kinase 5 and neurodegenerative diseases.Mol. Neurobiol.202461107287730210.1007/s12035‑024‑04047‑1 38378992
     [Google Scholar]
  50. BatraS. JahanS. AshrafA. AlharbyB. JawaidT. IslamA. HassanI. A review on cyclin-dependent kinase 5: An emerging drug target for neurodegenerative diseases.Int. J. Biol. Macromol.202323012325910.1016/j.ijbiomac.2023.123259 36641018
     [Google Scholar]
  51. TianZ. FengB. WangX.Q. TianJ. Focusing on cyclin-dependent kinases 5: A potential target for neurological disorders.Front. Mol. Neurosci.202215103063910.3389/fnmol.2022.1030639 36438186
     [Google Scholar]
  52. PrivesC. HallP.A. The p53 pathway.J. Pathol.1999187111212610.1002/(SICI)1096‑9896(199901)187:1<112:AID‑PATH250>3.0.CO;2‑3 10341712
     [Google Scholar]
  53. ChoY. GorinaS. JeffreyP.D. PavletichN.P. Crystal structure of a p53 tumor suppressor-DNA complex: Understanding tumorigenic mutations.Science1994265517034635510.1126/science.8023157 8023157
     [Google Scholar]
  54. SigalA. RotterV. Oncogenic mutations of the p53 tumor suppressor: The demons of the guardian of the genome.Cancer Res.2000602467886793 11156366
     [Google Scholar]
  55. KomoriT. OkamuraK. IkeharaM. YamamuroK. EndoN. OkumuraK. YamauchiT. IkawaD. Ouji-SageshimaN. ToritsukaM. TakadaR. KayashimaY. IshidaR. MoriY. KamikawaK. NoriyamaY. NishiY. ItoT. SaitoY. NishiM. KishimotoT. TanakaK.F. HiroiN. MakinodanM. Brain-derived neurotrophic factor from microglia regulates neuronal development in the medial prefrontal cortex and its associated social behavior.Mol. Psychiatry20242951338134910.1038/s41380‑024‑02413‑y 38243072
     [Google Scholar]
  56. AmidfarM. de OliveiraJ. KucharskaE. BudniJ. KimY.K. The role of CREB and BDNF in neurobiology and treatment of alzheimer’s disease.Life Sci.202025711802010.1016/j.lfs.2020.118020 32603820
     [Google Scholar]
  57. ArévaloJ.C. DeograciasR. Mechanisms controlling the expression and secretion of BDNF.Biomolecules202313578910.3390/biom13050789 37238659
     [Google Scholar]
  58. Josiane; Tatiani; Francielle; Michelle; Alexandra, The involvement of BDNF, NGF and GDNF in aging and alzheimer’s disease.Aging Dis.20156533134110.14336/AD.2015.0825 26425388
     [Google Scholar]
  59. PerroudN. SalzmannA. PradaP. NicastroR. HoeppliM-E. FurrerS. ArduS. KrejciI. KaregeF. MalafosseA. Response to psychotherapy in borderline personality disorder and methylation status of the BDNF gene.Transl. Psychiatry201331e207e20710.1038/tp.2012.140 23422958
     [Google Scholar]
  60. GaoL. ZhangY. SterlingK. SongW. Brain-derived neurotrophic factor in alzheimer’s disease and its pharmaceutical potential.Transl. Neurodegener.2022111410.1186/s40035‑022‑00279‑0 35090576
     [Google Scholar]
  61. CremonaC.A. BehrensA. ATM signalling and cancer.Oncogene201433263351336010.1038/onc.2013.275 23851492
     [Google Scholar]
  62. SmithJ. ThoL.M. XuN. GillespieD.A. The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer.Adv. Cancer Res.20101087311210.1016/B978‑0‑12‑380888‑2.00003‑0 21034966
     [Google Scholar]
  63. PhanL.M. RezaeianA.H. ATM: Main features, signaling pathways, and its diverse roles in DNA damage response, tumor suppression, and cancer development.Genes (Basel)202112684510.3390/genes12060845 34070860
     [Google Scholar]
  64. WeberA.M. RyanA.J. ATM and ATR as therapeutic targets in cancer.Pharmacol. Ther.201514912413810.1016/j.pharmthera.2014.12.001 25512053
     [Google Scholar]
  65. BeurelE. GriecoS.F. JopeR.S. Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases.Pharmacol. Ther.201514811413110.1016/j.pharmthera.2014.11.016 25435019
     [Google Scholar]
  66. JopeR. RohM.S. Glycogen synthase kinase-3 (GSK3) in psychiatric diseases and therapeutic interventions.Curr. Drug Targets20067111421143410.2174/1389450110607011421 17100582
     [Google Scholar]
  67. LiuJ. XiaoQ. XiaoJ. NiuC. LiY. ZhangX. ZhouZ. ShuG. YinG. Wnt/β-catenin signalling: Function, biological mechanisms, and therapeutic opportunities.Signal Transduct. Target. Ther.202271310.1038/s41392‑021‑00762‑6 34980884
     [Google Scholar]
  68. Eldar-FinkelmanH. MartinezA. GSK-3 inhibitors: Preclinical and clinical focus on CNS.Front. Mol. Neurosci.201143210.3389/fnmol.2011.00032 22065134
     [Google Scholar]
  69. KwakP.B. IwasakiS. TomariY. The microRNA pathway and cancer.Cancer Sci.2010101112309231510.1111/j.1349‑7006.2010.01683.x 20726859
     [Google Scholar]
  70. GulyaevaL.F. KushlinskiyN.E. Regulatory mechanisms of microRNA expression.J. Transl. Med.201614114310.1186/s12967‑016‑0893‑x 27197967
     [Google Scholar]
  71. HarmsK.L. ChenX. Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity.Cancer Res.20076773145315210.1158/0008‑5472.CAN‑06‑4397 17409421
     [Google Scholar]
  72. KarakostisK. Malbert-ColasL. ThermouA. VojtesekB. FåhraeusR. The DNA damage sensor ATM kinase interacts with the p53 mRNA and guides the DNA damage response pathway.Mol. Cancer20242312110.1186/s12943‑024‑01933‑z 38263180
     [Google Scholar]
  73. ProctorC.J. GrayD.A. GSK3 and p53 - Is there a link in alzheimer’s disease?Mol. Neurodegener.201051710.1186/1750‑1326‑5‑7 20181016
     [Google Scholar]
  74. GregorovaJ. Vychytilova-FaltejskovaP. SevcikovaS. Epigenetic regulation of MicroRNA clusters and families during tumor development.Cancers (Basel)2021136133310.3390/cancers13061333 33809566
     [Google Scholar]
  75. TanL. YuJ.T. TanL. Causes and consequences of microRNA dysregulation in neurodegenerative diseases.Mol. Neurobiol.20155131249126210.1007/s12035‑014‑8803‑9 24973986
     [Google Scholar]
  76. LaiK.O. WongA.S.L. CheungM.C. XuP. LiangZ. LokK.C. XieH. PalkoM.E. YungW.H. TessarolloL. CheungZ.H. IpN.Y. TrkB phosphorylation by Cdk5 is required for activity-dependent structural plasticity and spatial memory.Nat. Neurosci.201215111506151510.1038/nn.3237 23064382
     [Google Scholar]
  77. GräffJ. ReiD. GuanJ.S. WangW.Y. SeoJ. HennigK.M. NielandT.J.F. FassD.M. KaoP.F. KahnM. SuS.C. SamieiA. JosephN. HaggartyS.J. DelalleI. TsaiL.H. An epigenetic blockade of cognitive functions in the neurodegenerating brain.Nature2012483738822222610.1038/nature10849 22388814
     [Google Scholar]
  78. Medina-FrancoJ.L. GiulianottiM.A. WelmakerG.S. HoughtenR.A. Shifting from the single to the multitarget paradigm in drug discovery.Drug Discov. Today2013189-1049550110.1016/j.drudis.2013.01.008 23340113
     [Google Scholar]
  79. AnighoroA. BajorathJ. RastelliG. Polypharmacology: Challenges and opportunities in drug discovery.J. Med. Chem.201457197874788710.1021/jm5006463 24946140
     [Google Scholar]
  80. ZhouJ. JiangX. HeS. JiangH. FengF. LiuW. QuW. SunH. Rational design of multitarget-directed ligands: Strategies and emerging paradigms.J. Med. Chem.201962208881891410.1021/acs.jmedchem.9b00017 31082225
     [Google Scholar]
  81. NikolicK. MavridisL. DjikicT. VucicevicJ. AgbabaD. YelekciK. MitchellJ.B.O. Drug design for CNS diseases: Polypharmacological profiling of compounds using cheminformatic, 3d-qsar and virtual screening methodologies.Front. Neurosci.20161026510.3389/fnins.2016.00265 27375423
     [Google Scholar]
  82. BottegoniG. FaviaA.D. RecanatiniM. CavalliA. The role of fragment-based and computational methods in polypharmacology.Drug Discov. Today2012171-2233410.1016/j.drudis.2011.08.002 21864710
     [Google Scholar]
  83. MorphyR. RankovicZ. Designed multiple ligands. An emerging drug discovery paradigm.J. Med. Chem.200548216523654310.1021/jm058225d 16220969
     [Google Scholar]
  84. BondarevA.D. AttwoodM.M. JonssonJ. ChubarevV.N. TarasovV.V. SchiöthH.B. Recent developments of HDAC inhibitors: Emerging indications and novel molecules.Br. J. Clin. Pharmacol.202187124577459710.1111/bcp.14889 33971031
     [Google Scholar]
  85. TateC.R. RhodesL.V. SegarH.C. DriverJ.L. PounderF.N. BurowM.E. Collins-BurowB.M. Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat.Breast Cancer Res.2012143R7910.1186/bcr3192 22613095
     [Google Scholar]
  86. BeljkasM. IlicA. CebzanA. RadovicB. DjokovicN. RuzicD. NikolicK. OljacicS. Targeting histone deacetylases 6 in dual-target therapy of cancer.Pharmaceutics20231511258110.3390/pharmaceutics15112581 38004560
     [Google Scholar]
  87. RamsayR.R. Popovic-NikolicM.R. NikolicK. UliassiE. BolognesiM.L. A perspective on multi‐target drug discovery and design for complex diseases.Clin. Transl. Med.201871e310.1186/s40169‑017‑0181‑2 29340951
     [Google Scholar]
  88. MacalinoS.J.Y. GosuV. HongS. ChoiS. Role of computer-aided drug design in modern drug discovery.Arch. Pharm. Res.20153891686170110.1007/s12272‑015‑0640‑5 26208641
     [Google Scholar]
  89. SliwoskiG. KothiwaleS. MeilerJ. LoweE.W.Jr Computational methods in drug discovery.Pharmacol. Rev.201466133439510.1124/pr.112.007336 24381236
     [Google Scholar]
  90. VemulaD. JayasuryaP. SushmithaV. KumarY.N. BhandariV. CADD, AI and ML in drug discovery: A comprehensive review.Eur. J. Pharm. Sci.202318110632410.1016/j.ejps.2022.106324 36347444
     [Google Scholar]
  91. GaneP.J. DeanP.M. Recent advances in structure-based rational drug design.Curr. Opin. Struct. Biol.200010440140410.1016/S0959‑440X(00)00105‑6 10981625
     [Google Scholar]
  92. DawoodM. ElbadawiM. BöckersM. BringmannG. EfferthT. Molecular docking-based virtual drug screening revealing an oxofluorenyl benzamide and a bromonaphthalene sulfonamido hydroxybenzoic acid as HDAC6 inhibitors with cytotoxicity against leukemia cells.Biomed. Pharmacother.202012911045410.1016/j.biopha.2020.110454 32768947
     [Google Scholar]
  93. RiccardiL. GennaV. De VivoM. Metal–ligand interactions in drug design.Nat. Rev. Chem.20182710011210.1038/s41570‑018‑0018‑6
     [Google Scholar]
  94. AjjarapuS.M. TiwariA. RamtekeP.W. SinghD.B. KumarS. Ligand-based drug designing.Academic Press202210.1016/B978‑0‑323‑89775‑4.00018‑3
     [Google Scholar]
  95. WilsonG.L. LillM.A. Integrating structure-based and ligand-based approaches for computational drug design.Future Med. Chem.20113673575010.4155/fmc.11.18 21554079
     [Google Scholar]
  96. FerreiraL. Dos SantosR. OlivaG. AndricopuloA. Molecular docking and structure-based drug design strategies.Molecules2015207133841342110.3390/molecules200713384 26205061
     [Google Scholar]
  97. OdaA. SaijoK. IshiokaC. NaritaK. KatohT. WatanabeY. FukuyoshiS. TakahashiO. TakahashiO. Predicting the structures of complexes between phosphoinositide 3-kinase (PI3K) and romidepsin-related compounds for the drug design of PI3K/histone deacetylase dual inhibitors using computational docking and the ligand-based drug design approach.J. Mol. Graph. Model.201454465310.1016/j.jmgm.2014.08.007 25254927
     [Google Scholar]
  98. FrumanD.A. MeyersR.E. CantleyL.C. Phosphoinositide kinases.Annu. Rev. Biochem.199867148150710.1146/annurev.biochem.67.1.481 9759495
     [Google Scholar]
  99. SamuelsY. WangZ. BardelliA. SillimanN. PtakJ. SzaboS. YanH. GazdarA. PowellS.M. RigginsG.J. WillsonJ.K.V. MarkowitzS. KinzlerK.W. VogelsteinB. VelculescuV.E. High frequency of mutations of the PIK3CA gene in human cancers.Science2004304567055455410.1126/science.1096502 15016963
     [Google Scholar]
  100. FanQ.W. ChengC.K. NicolaidesT.P. KnightZ.A. ShokatK.M. WeissW.A. A dual PI3K α/mTOR inhibitor cooperates with blockade of EGFR in PTEN-mutant glioma.Cancer Res.20076717796010.1158/0008‑5472.CAN‑07‑2154 17804702
     [Google Scholar]
  101. SosM.L. FischerS. UllrichR. PeiferM. HeuckmannJ.M. KokerM. HeynckS. StückrathI. WeissJ. FischerF. MichelK. GoelA. RegalesL. PolitiK.A. PereraS. GetlikM. HeukampL.C. AnsénS. ZanderT. BeroukhimR. KashkarH. ShokatK.M. SellersW.R. RauhD. OrrC. HoeflichK.P. FriedmanL. WongK.K. PaoW. ThomasR.K. Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer.Proc. Natl. Acad. Sci. USA200910643183511835610.1073/pnas.0907325106 19805051
     [Google Scholar]
  102. WeeS. JaganiZ. XiangK.X. LooA. DorschM. YaoY.M. SellersW.R. LengauerC. StegmeierF. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers.Cancer Res.200969104286429310.1158/0008‑5472.CAN‑08‑4765 19401449
     [Google Scholar]
  103. QianC. LaiC.J. BaoR. WangD.G. WangJ. XuG.X. AtoyanR. QuH. YinL. SamsonM. ZifcakB. MaA.W.S. DellaRoccaS. BorekM. ZhaiH.X. CaiX. VoiM. Cancer network disruption by a single molecule inhibitor targeting both histone deacetylase activity and phosphatidylinositol 3-kinase signaling.Clin. Cancer Res.201218154104411310.1158/1078‑0432.CCR‑12‑0055 22693356
     [Google Scholar]
  104. WozniakM.B. VilluendasR. BischoffJ.R. AparicioC.B. Martínez LealJ.F. de La CuevaP. RodriguezM.E. HerrerosB. Martin-PerezD. LongoM.I. HerreraM. PirisM.A. Ortiz-RomeroP.L. Vorinostat interferes with the signaling transduction pathway of T-cell receptor and synergizes with phosphoinositide-3 kinase inhibitors in cutaneous T-cell lymphoma.Haematologica201095461362110.3324/haematol.2009.013870 20133897
     [Google Scholar]
  105. YounesA. BerdejaJ.G. PatelM.R. FlinnI. GerecitanoJ.F. NeelapuS.S. KellyK.R. CopelandA.R. AkinsA. ClancyM.S. GongL. WangJ. MaA. VinerJ.L. OkiY. Phase 1 safety and dose escalation of CUDC-907, a first-in-class, oral, dual inhibitor of HDAC and PI3K in relapsed or refractory lymphoma and multiple myeloma.Lancet Oncol.201617562210.1016/S1470‑2045(15)00584‑7 27049457
     [Google Scholar]
  106. ReddyS.A. Romidepsin for the treatment of relapsed/refractory cutaneous T-cell lymphoma (mycosis fungoides/Sézary syndrome): Use in a community setting.Crit. Rev. Oncol. Hematol.20161069910710.1016/j.critrevonc.2016.07.001 27637355
     [Google Scholar]
  107. SaijoK. KatohT. ShimodairaH. OdaA. TakahashiO. IshiokaC. Romidepsin (FK 228) and its analogs directly inhibit phosphatidylinositol 3‐kinase activity and potently induce apoptosis as histone deacetylase/phosphatidylinositol 3‐kinase dual inhibitors.Cancer Sci.2012103111994200110.1111/cas.12002 22924958
     [Google Scholar]
  108. YuanZ. SunQ. LiD. MiaoS. ChenS. SongL. GaoC. ChenY. TanC. JiangY. Design, synthesis and anticancer potential of NSC-319745 hydroxamic acid derivatives as DNMT and HDAC inhibitors.Eur. J. Med. Chem.201713428129210.1016/j.ejmech.2017.04.017 28419930
     [Google Scholar]
  109. KuckD. SinghN. LykoF. Medina-FrancoJ.L. Novel and selective DNA methyltransferase inhibitors: Docking-based virtual screening and experimental evaluation.Bioorg. Med. Chem.201018282282910.1016/j.bmc.2009.11.050 20006515
     [Google Scholar]
  110. ChenS. WangY. ZhouW. LiS. PengJ. ShiZ. HuJ. LiuY.C. DingH. LinY. LiL. ChengS. LiuJ. LuT. JiangH. LiuB. ZhengM. LuoC. Identifying novel selective non-nucleoside DNA methyltransferase 1 inhibitors through docking-based virtual screening.J. Med. Chem.201457219028904110.1021/jm501134e 25333769
     [Google Scholar]
  111. MarksP.A. BreslowR. Dimethyl sulfoxide to vorinostat: Development of this histone deacetylase inhibitor as an anticancer drug.Nat. Biotechnol.2007251849010.1038/nbt1272 17211407
     [Google Scholar]
  112. YuanZ. ChenS. GaoC. DaiQ. ZhangC. SunQ. LinJ.S. GuoC. ChenY. JiangY. Development of a versatile DNMT and HDAC inhibitor C02S modulating multiple cancer hallmarks for breast cancer therapy.Bioorg. Chem.20198720020810.1016/j.bioorg.2019.03.027 30901675
     [Google Scholar]
  113. Prieto-MartínezF.D. Fernández-de GortariE. Medina-FrancoJ.L. Espinoza-FonsecaL.M. An in silico pipeline for the discovery of multitarget ligands: A case study for epi-polypharmacology based on DNMT1/HDAC2 inhibition.Artif. Intell. Life Sci.20211
     [Google Scholar]
  114. LaiC.J. BaoR. TaoX. WangJ. AtoyanR. QuH. WangD.G. YinL. SamsonM. ForresterJ. ZifcakB. XuG.X. DellaRoccaS. ZhaiH.X. CaiX. MungerW.E. KeeganM. PepicelliC.V. QianC. CUDC-101, a multitargeted inhibitor of histone deacetylase, epidermal growth factor receptor, and human epidermal growth factor receptor 2, exerts potent anticancer activity.Cancer Res.20107093647365610.1158/0008‑5472.CAN‑09‑3360 20388807
     [Google Scholar]
  115. BaiX. SunP. WangX. LongC. LiaoS. DangS. ZhuangS. DuY. ZhangX. LiN. HeK. ZhangZ. Structure and dynamics of the EGFR/HER2 heterodimer.Cell Discov.2023911810.1038/s41421‑023‑00523‑5 36781849
     [Google Scholar]
  116. SeshacharyuluP. PonnusamyM.P. HaridasD. JainM. GantiA.K. BatraS.K. Targeting the EGFR signaling pathway in cancer therapy.Expert Opin. Ther. Targets2012161153110.1517/14728222.2011.648617 22239438
     [Google Scholar]
  117. ChuangD.M. LengY. MarinovaZ. KimH.J. ChiuC.T. Multiple roles of HDAC inhibition in neurodegenerative conditions.Trends Neurosci.2009321159160110.1016/j.tins.2009.06.002 19775759
     [Google Scholar]
  118. ReisbergB. DoodyR. StöfflerA. SchmittF. FerrisS. MöbiusH.J. Memantine in moderate-to-severe alzheimer’s disease.N. Engl. J. Med.2003348141333134110.1056/NEJMoa013128 12672860
     [Google Scholar]
  119. HeF. RanY. LiX. WangD. ZhangQ. LvJ. YuC. QuY. ZhangX. XuA. WeiC. ChouC.J. WuJ. Design, synthesis and biological evaluation of dual-function inhibitors targeting NMDAR and HDAC for alzheimer’s disease.Bioorg. Chem.202010310410910.1016/j.bioorg.2020.104109 32768741
     [Google Scholar]
  120. StreblM.G. WangC. SchroederF.A. PlaczekM.S. WeyH.Y. Van de BittnerG.C. NeelamegamR. HookerJ.M. Development of a fluorinated class-I HDAC radiotracer reveals key chemical determinants of brain penetrance.ACS Chem. Neurosci.20167552853310.1021/acschemneuro.5b00297 26675505
     [Google Scholar]
  121. TallantC. MarreroA. Gomis-RüthF.X. Matrix metalloproteinases: Fold and function of their catalytic domains.Biochim. Biophys. Acta Mol. Cell Res.201018031202810.1016/j.bbamcr.2009.04.003 19374923
     [Google Scholar]
  122. OverallC.M. López-OtínC. Strategies for MMP inhibition in cancer: Innovations for the post-trial era.Nat. Rev. Cancer20022965767210.1038/nrc884 12209155
     [Google Scholar]
  123. HalderA.K. MallickS. ShikhaD. SahaA. SahaK.D. JhaT. Design of dual MMP-2/HDAC-8 inhibitors by pharmacophore mapping, molecular docking, synthesis and biological activity.RSC Advances2015588723737238610.1039/C5RA12606A
     [Google Scholar]
  124. MittalK. EbosJ. RiniB. Angiogenesis and the tumor microenvironment: Vascular endothelial growth factor and beyond.Semin. Oncol.201441223525110.1053/j.seminoncol.2014.02.007 24787295
     [Google Scholar]
  125. ParkC. JunJ.A. JeongK.J. HeoH.J. SohnJ.S. LeeH.Y. ParkC.G. KangJ. Histone deacetylases 1, 6 and 8 are critical for invasion in breast cancer.Oncol. Rep.20112561677168110.3892/or.2011.1236 21455583
     [Google Scholar]
  126. LiuL.T. ChangH.C. ChiangL.C. HungW.C. Histone deacetylase inhibitor up-regulates RECK to inhibit MMP-2 activation and cancer cell invasion.Cancer Res.2003631230693072 12810630
     [Google Scholar]
  127. HalderA.K. SahaA. JhaT. Exploring QSAR and pharmacophore mapping of structurally diverse selective matrix metalloproteinase-2 inhibitors.J. Pharm. Pharmacol.201365101541155410.1111/jphp.12133 24028622
     [Google Scholar]
  128. VenkatesanA.M. DavisJ.M. GrosuG.T. BakerJ. ZaskA. LevinJ.I. EllingboeJ. SkotnickiJ.S. DiJosephJ.F. SungA. JinG. XuW. McCarthyD.J. BaroneD. Synthesis and structure-activity relationships of 4-alkynyloxy phenyl sulfanyl, sulfinyl, and sulfonyl alkyl hydroxamates as tumor necrosis factor-α converting enzyme and matrix metalloproteinase inhibitors.J. Med. Chem.200447256255626910.1021/jm040086x 15566296
     [Google Scholar]
  129. VermaR.P. HanschC. Matrix metalloproteinases (MMPs): Chemical–biological functions and (Q)SARs.Bioorg. Med. Chem.20071562223226810.1016/j.bmc.2007.01.011 17275314
     [Google Scholar]
  130. VargováV. PytliakM. MechírováV. Matrix metalloproteinases. Matrix metalloproteinase inhibitors: Specificity of binding and structure-activity relationships, Matrix Metalloproteinases.Matrix Metalloproteinase Inhibitors GuptaS. Experientia Supplementum2012Vol. 10313310.1007/978‑3‑0348‑0364‑9_1
     [Google Scholar]
  131. ValenteS. MaiA. Small-molecule inhibitors of histone deacetylase for the treatment of cancer and non-cancer diseases: A patent review (2011 – 2013).Expert Opin. Ther. Pat.201424440141510.1517/13543776.2014.877446 24397271
     [Google Scholar]
  132. SeclìL. AvalleL. PoggioP. FragaleG. CannataC. ContiL. IannucciA. CarràG. RubinettoC. MiniscalcoB. HirschE. PoliV. MorottiA. De AndreaM. TurcoE. CavalloF. FusellaF. BrancaccioM. Targeting the extracellular HSP90 co-chaperone morgana inhibits cancer cell migration and promotes anticancer immunity.Cancer Res.202181184794480710.1158/0008‑5472.CAN‑20‑3150 34193441
     [Google Scholar]
  133. WuJ. LiuT. RiosZ. MeiQ. LinX. CaoS. Heat shock proteins and cancer.Trends Pharmacol. Sci.201738322625610.1016/j.tips.2016.11.009 28012700
     [Google Scholar]
  134. MahalingamD. SwordsR. CarewJ.S. NawrockiS.T. BhallaK. GilesF.J. Targeting HSP90 for cancer therapy.Br. J. Cancer2009100101523152910.1038/sj.bjc.6605066 19401686
     [Google Scholar]
  135. WeiH. ZhangY. JiaY. ChenX. NiuT. ChatterjeeA. HeP. HouG. Heat shock protein 90: Biological functions, diseases, and therapeutic targets.MedComm202452e47010.1002/mco2.470 38283176
     [Google Scholar]
  136. PinziL. BenedettiR. AltucciL. RastelliG. Design of dual inhibitors of histone deacetylase 6 and heat shock protein 90.ACS Omega2020520114731148010.1021/acsomega.0c00559 32478236
     [Google Scholar]
  137. BonanniD. CitarellaA. MoiD. PinziL. BergaminiE. RastelliG. Dual targeting strategies on histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90).Curr. Med. Chem.20222991474150210.2174/0929867328666210902145102 34477503
     [Google Scholar]
  138. KovacsJ.J. MurphyP.J.M. GaillardS. ZhaoX. WuJ.T. NicchittaC.V. YoshidaM. ToftD.O. PrattW.B. YaoT.P. HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.Mol. Cell200518560160710.1016/j.molcel.2005.04.021 15916966
     [Google Scholar]
  139. MurphyP.J.M. MorishimaY. KovacsJ.J. YaoT.P. PrattW.B. Regulation of the dynamics of hsp90 action on the glucocorticoid receptor by acetylation/deacetylation of the chaperone.J. Biol. Chem.200528040337923379910.1074/jbc.M506997200 16087666
     [Google Scholar]
  140. KovacsJ.J. CohenT.J. YaoT.P. Chaperoning steroid hormone signaling via reversible acetylation.Nucl. Recept. Signal.200531nrs.0300410.1621/nrs.03004 16604172
     [Google Scholar]
  141. Trifluoromethyl-oxadiazole derivatives and their use in the treatment of diseasePatent US-9056843-B22023
  142. Recillas-TargaF. Cancer epigenetics: An overview.Arch. Med. Res.202253873274010.1016/j.arcmed.2022.11.003 36411173
     [Google Scholar]
  143. WuY. SarkissyanM. VadgamaJ.V. Epigenetics in breast and prostate cancer.Methods Mol. Biol.2015123842546610.1007/978‑1‑4939‑1804‑1_23 25421674
     [Google Scholar]
  144. Lopez-BertoniH. LalB. LiA. CaplanM. Guerrero-CázaresH. EberhartC.G. Quiñones-HinojosaA. GlasM. SchefflerB. LaterraJ. LiY. DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2.Oncogene201534303994400410.1038/onc.2014.334 25328136
     [Google Scholar]
  145. HuangW. LiH. YuQ. XiaoW. WangD.O. Correction: LncRNA-mediated DNA methylation: An emerging mechanism in cancer and beyond.J. Exp. Clin. Cancer Res.202241126210.1186/s13046‑022‑02468‑1 36028910
     [Google Scholar]
  146. LiY. SetoE. HDACs and HDAC inhibitors in cancer development and therapy.Cold Spring Harb. Perspect. Med.2016610a02683110.1101/cshperspect.a026831 27599530
     [Google Scholar]
  147. ChengB. PanW. XiaoY. DingZ. ZhouY. FeiX. LiuJ. SuZ. PengX. ChenJ. HDAC-targeting epigenetic modulators for cancer immunotherapy.Eur. J. Med. Chem.202426511612910.1016/j.ejmech.2024.116129 38211468
     [Google Scholar]
  148. HoldgateG.A. BardelleC. LanneA. ReadJ. O’DonovanD.H. SmithJ.M. SelmiN. SheppardR. Drug discovery for epigenetics targets.Drug Discov. Today20222741088109810.1016/j.drudis.2021.10.020 34728375
     [Google Scholar]
  149. JanZ. AhmedW.S. BiswasK.H. JitheshP.V. Identification of a potential DNA methyltransferase (DNMT) inhibitor.J. Biomol. Struct. Dyn.202311510.1080/07391102.2023.2233637 37424222
     [Google Scholar]
  150. HellebrekersD.M.E.I. GriffioenA.W. van EngelandM. Dual targeting of epigenetic therapy in cancer.Biochim. Biophys. Acta Rev. Cancer200717751769110.1016/j.bbcan.2006.07.003 16930846
     [Google Scholar]
  151. PommierY. SunY. HuangS.N. NitissJ.L. Roles of eukaryotic topoisomerases in transcription, replication and genomic stability.Nat. Rev. Mol. Cell Biol.2016171170372110.1038/nrm.2016.111 27649880
     [Google Scholar]
  152. ChampouxJ.J. DNA topoisomerases: Structure, function, and mechanism.Annu. Rev. Biochem.200170136941310.1146/annurev.biochem.70.1.369 11395412
     [Google Scholar]
  153. MadkourM.M. RamadanW.S. SalehE. El-AwadyR. Epigenetic modulations in cancer: Predictive biomarkers and potential targets for overcoming the resistance to topoisomerase I inhibitors.Ann. Med.2023551220394610.1080/07853890.2023.2203946 37092854
     [Google Scholar]
  154. CandelariaM. Gallardo-RincónD. ArceC. CetinaL. Aguilar-PonceJ.L. ArrietaÓ. González-FierroA. Chávez-BlancoA. de la Cruz-HernándezE. CamargoM.F. Trejo-BecerrilC. Pérez-CárdenasE. Pérez-PlasenciaC. Taja-ChayebL. Wegman-OstroskyT. Revilla-VazquezA. Dueñas-GonzálezA. A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors.Ann. Oncol.20071891529153810.1093/annonc/mdm204 17761710
     [Google Scholar]
  155. ChenJ. LiD. LiW. YinJ. ZhangY. YuanZ. GaoC. LiuF. JiangY. Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors.Bioorg. Med. Chem.201826143958396610.1016/j.bmc.2018.06.016 29954683
     [Google Scholar]
  156. GlavianoA. FooA.S.C. LamH.Y. YapK.C.H. JacotW. JonesR.H. EngH. NairM.G. MakvandiP. GeoergerB. KulkeM.H. BairdR.D. PrabhuJ.S. CarboneD. PecoraroC. TehD.B.L. SethiG. CavalieriV. LinK.H. Javidi-SharifiN.R. ToskaE. DavidsM.S. BrownJ.R. DianaP. StebbingJ. FrumanD.A. KumarA.P. PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer.Mol. Cancer202322113810.1186/s12943‑023‑01827‑6 37596643
     [Google Scholar]
  157. ErsahinT. TuncbagN. Cetin-AtalayR. The PI3K/AKT/mTOR interactive pathway.Mol. Biosyst.20151171946195410.1039/C5MB00101C 25924008
     [Google Scholar]
  158. PortaC. PaglinoC. MoscaA. Targeting PI3K/Akt/mTOR signaling in cancer.Front. Oncol.201446410.3389/fonc.2014.00064 24782981
     [Google Scholar]
  159. ChenY. ZhouX. Research progress of mTOR inhibitors.Eur. J. Med. Chem.202020811282010.1016/j.ejmech.2020.112820 32966896
     [Google Scholar]
  160. WaniA.K. SinghR. AkhtarN. PrakashA. NepovimovaE. OleksakP. ChrienovaZ. AlomarS. ChopraC. KucaK. Targeted inhibition of the PI3K/Akt/mTOR signaling axis: Potential for sarcoma therapy.Mini Rev. Med. Chem.202424161496152010.2174/0113895575270904231129062137 38265369
     [Google Scholar]
  161. WedelS. HudakL. SeibelJ.M. JuengelE. TsaurI. WiesnerC. HaferkampA. BlahetaR.A. Inhibitory effects of the HDAC inhibitor valproic acid on prostate cancer growth are enhanced by simultaneous application of the mTOR inhibitor RAD001.Life Sci.2011889-1041842410.1016/j.lfs.2010.12.017 21192952
     [Google Scholar]
  162. ZhangA. LauN.A. WongA. BrownL.G. ColemanI.M. De SarkarN. LiD. DeLuciaD.C. LabrecqueM.P. NguyenH.M. ConnerJ.L. DumpitR.F. TrueL.D. LinD.W. CoreyE. AlumkalJ.J. NelsonP.S. MorrisseyC. LeeJ.K. Concurrent targeting of HDAC and PI3K to Overcome phenotypic heterogeneity of castration-resistant and neuroendocrine prostate cancers.Cancer Res. Commun.20233112358237410.1158/2767‑9764.CRC‑23‑0250 37823778
     [Google Scholar]
  163. ŞansaçarM. SağırH. Gencer AkçokE.B. Inhibition of PI3K-AKT-mTOR pathway and modulation of histone deacetylase enzymes reduce the growth of acute myeloid leukemia cells.Med. Oncol.20234113110.1007/s12032‑023‑02247‑8 38148433
     [Google Scholar]
  164. MahalingamD. MedinaE.C. EsquivelJ.A.II EspitiaC.M. SmithS. OberheuK. SwordsR. KellyK.R. MitaM.M. MitaA.C. CarewJ.S. GilesF.J. NawrockiS.T. Vorinostat enhances the activity of temsirolimus in renal cell carcinoma through suppression of survivin levels.Clin. Cancer Res.201016114115310.1158/1078‑0432.CCR‑09‑1385 20028765
     [Google Scholar]
  165. ZhangM. WeiW. PengC. MaX. HeX. ZhangH. ZhouM. Discovery of novel pyrazolopyrimidine derivatives as potent mTOR/HDAC bi-functional inhibitors via pharmacophore-merging strategy.Bioorg. Med. Chem. Lett.20214912828610.1016/j.bmcl.2021.128286 34314844
     [Google Scholar]
  166. LandsburgD.J. BartaS.K. RamchandrenR. BatleviC. IyerS. KellyK. MicallefI.N. SmithS.M. StevensD.A. AlvarezM. CalifanoA. ShenY. BoskerG. ParkerJ. SoikesR. MartinezE. von RoemelingR. MartellR.E. OkiY. Fimepinostat (CUDC‐907) in patients with relapsed/refractory diffuse large B cell and high‐grade B‐cell lymphoma: Report of a phase 2 trial and exploratory biomarker analyses.Br. J. Haematol.2021195220120910.1111/bjh.17730 34341990
     [Google Scholar]
  167. ChenY. WangX. XiangW. HeL. TangM. WangF. WangT. YangZ. YiY. WangH. NiuT. ZhengL. LeiL. LiX. SongH. ChenL. Development of purine-based hydroxamic acid derivatives: Potent histone deacetylase inhibitors with marked in vitro and in vivo antitumor activities.J. Med. Chem.201659115488550410.1021/acs.jmedchem.6b00579 27186676
     [Google Scholar]
  168. ChenD. SohC.K. GohW.H. WangH. Design, synthesis, and preclinical evaluation of fused pyrimidine-based hydroxamates for the treatment of hepatocellular carcinoma.J. Med. Chem.20186141552157510.1021/acs.jmedchem.7b01465 29360358
     [Google Scholar]
  169. LinS. WangC. JiM. WuD. LvY. ZhangK. DongY. JinJ. ChenJ. ZhangJ. ShengL. LiY. ChenX. XuH. Discovery and optimization of 2-Amino-4-methylquinazoline derivatives as highly potent Phosphatidylinositol 3-Kinase inhibitors for cancer treatment.J. Med. Chem.201861146087610910.1021/acs.jmedchem.8b00416 29927604
     [Google Scholar]
  170. ZhangK. LaiF. LinS. JiM. ZhangJ. ZhangY. JinJ. FuR. WuD. TianH. XueN. ShengL. ZouX. LiY. ChenX. XuH. Design, synthesis, and biological evaluation of 4-Methyl quinazoline derivatives as anticancer agents simultaneously targeting Phosphoinositide 3-Kinases and histone deacetylases.J. Med. Chem.201962156992701410.1021/acs.jmedchem.9b00390 31117517
     [Google Scholar]
  171. ZhangK. HuangR. JiM. LinS. LaiF. WuD. TianH. BiJ. PengS. HuJ. ShengL. LiY. ChenX. XuH. Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia.Eur. J. Med. Chem.202426411601510.1016/j.ejmech.2023.116015 38048697
     [Google Scholar]
  172. NussinovR. TsaiC.J. JangH. Anticancer drug resistance: An update and perspective.Drug Resist. Updat.20215910079610.1016/j.drup.2021.100796 34953682
     [Google Scholar]
  173. TangY. ZangH. WenQ. FanS. AXL in cancer: A modulator of drug resistance and therapeutic target.J. Exp. Clin. Cancer Res.202342114810.1186/s13046‑023‑02726‑w 37328828
     [Google Scholar]
  174. ZhuC. WeiY. WeiX. AXL receptor tyrosine kinase as a promising anti-cancer approach: Functions, molecular mechanisms and clinical applications.Mol. Cancer201918115310.1186/s12943‑019‑1090‑3 31684958
     [Google Scholar]
  175. FalconeI. ConciatoriF. BazzichettoC. BriaE. CarbogninL. MalagutiP. FerrettiG. CognettiF. MilellaM. CiuffredaL. AXL receptor in breast cancer: Molecular involvement and therapeutic limitations.Int. J. Mol. Sci.20202122841910.3390/ijms21228419 33182542
     [Google Scholar]
  176. TanakaM. SiemannD.W. Therapeutic targeting of the Gas6/Axl signaling pathway in cancer.Int. J. Mol. Sci.20212218995310.3390/ijms22189953 34576116
     [Google Scholar]
  177. Ben-BatallaI. ErdmannR. JørgensenH. MitchellR. ErnstT. von AmsbergG. SchafhausenP. VelthausJ.L. RankinS. ClarkR.E. KoschmiederS. SchultzeA. MitraS. VandenbergheP. BrümmendorfT.H. CarmelietP. HochhausA. PantelK. BokemeyerC. HelgasonG.V. HolyoakeT.L. LogesS. Axl blockade by BGB324 inhibits BCR-ABL tyrosine kinase inhibitor–sensitive and -resistant chronic myeloid leukemia.Clin. Cancer Res.20172392289230010.1158/1078‑0432.CCR‑16‑1930 27856601
     [Google Scholar]
  178. QiaoX. WuX. ChenS. NiuM.M. HuaH. ZhangY. Discovery of novel and potent dual-targeting AXL/HDAC2 inhibitors for colorectal cancer treatment via structure-based pharmacophore modelling, virtual screening, and molecular docking, molecular dynamics simulation studies, and biological evaluation.J. Enzyme Inhib. Med. Chem.2024391229524110.1080/14756366.2023.2295241 38134358
     [Google Scholar]
  179. ScheltensP. De StrooperB. KivipeltoM. HolstegeH. ChételatG. TeunissenC.E. CummingsJ. van der FlierW.M. Alzheimer’s disease.Lancet2021397102841577159010.1016/S0140‑6736(20)32205‑4 33667416
     [Google Scholar]
  180. WellerJ. BudsonA. Current understanding of alzheimer’s disease diagnosis and treatment.F1000 Res.20187F100010.12688/f1000research.14506.1
     [Google Scholar]
  181. YangS. ZhangR. WangG. ZhangY. The development prospection of HDAC inhibitors as a potential therapeutic direction in alzheimer’s disease.Transl. Neurodegener.2017611910.1186/s40035‑017‑0089‑1 28702178
     [Google Scholar]
  182. SantanaD.A. SmithM.A.C. ChenE.S. Histone modifications in alzheimer’s disease.Genes (Basel)202314234710.3390/genes14020347 36833274
     [Google Scholar]
  183. NabaviS.M. TalarekS. ListosJ. NabaviS.F. DeviK.P. Roberto de OliveiraM. TewariD. ArgüellesS. MehrzadiS. HosseinzadehA. D’onofrioG. OrhanI.E. SuredaA. XuS. MomtazS. FarzaeiM.H. Phosphodiesterase inhibitors say NO to alzheimer’s disease.Food Chem. Toxicol.201913411082210.1016/j.fct.2019.110822 31536753
     [Google Scholar]
  184. XiM. SunT. ChaiS. XieM. ChenS. DengL. DuK. ShenR. SunH. Therapeutic potential of phosphodiesterase inhibitors for cognitive amelioration in alzheimer’s disease.Eur. J. Med. Chem.202223211417010.1016/j.ejmech.2022.114170 35144038
     [Google Scholar]
  185. García-BarrosoC. RicobarazaA. Pascual-LucasM. UncetaN. RicoA.J. GoicoleaM.A. SallésJ. LanciegoJ.L. OyarzabalJ. FrancoR. Cuadrado-TejedorM. García-OstaA. Tadalafil crosses the blood–brain barrier and reverses cognitive dysfunction in a mouse model of AD.Neuropharmacology20136411412310.1016/j.neuropharm.2012.06.052 22776546
     [Google Scholar]
  186. SandersO. Sildenafil for the treatment of alzheimer’s disease: A systematic review.J. Alzheimers Dis. Rep.2020419110610.3233/ADR‑200166 32467879
     [Google Scholar]
  187. AthiraK.V. SadanandanP. ChakravartyS. Repurposing vorinostat for the treatment of disorders affecting brain.Neuromolecular Med.202123444946510.1007/s12017‑021‑08660‑4 33948878
     [Google Scholar]
  188. KumarV. KunduS. SinghA. SinghS. Understanding the role of histone deacetylase and their inhibitors in neurodegenerative disorders: Current targets and future perspective.Curr. Neuropharmacol.202220115817810.2174/1570159X19666210609160017 34151764
     [Google Scholar]
  189. Cuadrado-TejedorM. Garcia-BarrosoC. Sánchez-AriasJ.A. RabalO. Pérez-GonzálezM. MederosS. UgarteA. FrancoR. SeguraV. PereaG. OyarzabalJ. Garcia-OstaA. A first-in-class small-molecule that acts as a dual inhibitor of hdac and pde5 and that rescues hippocampal synaptic impairment in alzheimer’s disease mice.Neuropsychopharmacology201742252453910.1038/npp.2016.163 27550730
     [Google Scholar]
  190. RabalO. Sánchez-AriasJ.A. Cuadrado-TejedorM. de MiguelI. Pérez-GonzálezM. García-BarrosoC. UgarteA. Estella-Hermoso de MendozaA. SáezE. EspelosinM. UrsuaS. HaizhongT. WeiW. MushengX. Garcia-OstaA. OyarzabalJ. Design, synthesis, biological evaluation and in vivo testing of dual phosphodiesterase 5 (PDE5) and histone deacetylase 6 (HDAC6)-selective inhibitors for the treatment of alzheimer’s disease.Eur. J. Med. Chem.201815050652410.1016/j.ejmech.2018.03.005 29549837
     [Google Scholar]
  191. RabalO. Sánchez-AriasJ.A. Cuadrado-TejedorM. de MiguelI. Pérez-GonzálezM. García-BarrosoC. UgarteA. Estella-Hermoso de MendozaA. SáezE. EspelosinM. UrsuaS. HaizhongT. WeiW. MushengX. Garcia-OstaA. OyarzabalJ. Discovery of in vivo chemical probes for treating alzheimer’s disease: Dual Phosphodiesterase 5 (PDE5) and Class I histone deacetylase selective inhibitors.ACS Chem. Neurosci.20191031765178210.1021/acschemneuro.8b00648 30525452
     [Google Scholar]
  192. ZhangF. SuB. WangC. SiedlakS.L. Mondragon-RodriguezS. LeeH. WangX. PerryG. ZhuX. Posttranslational modifications of α-tubulin in alzheimer disease.Transl. Neurodegener.201541910.1186/s40035‑015‑0030‑4 26029362
     [Google Scholar]
  193. KandothC. McLellanM.D. VandinF. YeK. NiuB. LuC. XieM. ZhangQ. McMichaelJ.F. WyczalkowskiM.A. LeisersonM.D.M. MillerC.A. WelchJ.S. WalterM.J. WendlM.C. LeyT.J. WilsonR.K. RaphaelB.J. DingL. Mutational landscape and significance across 12 major cancer types.Nature2013502747133333910.1038/nature12634 24132290
     [Google Scholar]
  194. XiongS. Mouse models of Mdm2 and Mdm4 and their clinical implications.Chin. J. Cancer201332737137510.5732/cjc.012.10286 23327795
     [Google Scholar]
  195. KooN. SharmaA.K. NarayanS. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death.Int. J. Mol. Sci.2022239500510.3390/ijms23095005 35563397
     [Google Scholar]
  196. GuerlavaisV. SawyerT.K. CarvajalL. ChangY.S. GravesB. RenJ.G. SuttonD. OlsonK.A. PackmanK. DarlakK. ElkinC. FeyfantE. KesavanK. GangurdeP. VassilevL.T. NashH.M. VukovicV. AivadoM. AnnisD.A. Discovery of Sulanemadlin (ALRN-6924), the first cell-permeating, stabilized α-Helical peptide in clinical development.J. Med. Chem.202366149401941710.1021/acs.jmedchem.3c00623 37439511
     [Google Scholar]
  197. PairawanS. ZhaoM. YucaE. AnnisA. EvansK. SuttonD. CarvajalL. RenJ.G. SantiagoS. GuerlavaisV. AkcakanatA. TapiaC. YangF. BoseP.S.C. ZhengX. DumbravaE.I. AivadoM. Meric-BernstamF. First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models.Breast Cancer Res.20212312910.1186/s13058‑021‑01406‑x 33663585
     [Google Scholar]
  198. NunesR.C. RibeiroC.J.A. MonteiroÂ. RodriguesC.M.P. AmaralJ.D. SantosM.M.M. In vitro targeting of colon cancer cells using spiropyrazoline oxindoles.Eur. J. Med. Chem.201713916817910.1016/j.ejmech.2017.07.057 28800455
     [Google Scholar]
  199. EspadinhaM. LopesE.A. MarquesV. AmaralJ.D. dos SantosD.J.V.A. MoriM. DanieleS. PiccarducciR. ZappelliE. MartiniC. RodriguesC.M.P. SantosM.M.M. Discovery of MDM2-p53 and MDM4-p53 protein-protein interactions small molecule dual inhibitors.Eur. J. Med. Chem.202224111463710.1016/j.ejmech.2022.114637 35961068
     [Google Scholar]
  200. YaoQ. ChenY. ZhouX. The roles of microRNAs in epigenetic regulation.Curr. Opin. Chem. Biol.201951111710.1016/j.cbpa.2019.01.024 30825741
     [Google Scholar]
  201. LuT.X. RothenbergM.E. MicroRNA.J. Allergy Clin. Immunol.201814141202120710.1016/j.jaci.2017.08.034 29074454
     [Google Scholar]
  202. Ferragut CardosoA.P. BanerjeeM. NailA.N. LykoudiA. StatesJ.C. miRNA dysregulation is an emerging modulator of genomic instability.Semin. Cancer Biol.20217612013110.1016/j.semcancer.2021.05.004 33979676
     [Google Scholar]
  203. DienerC. KellerA. MeeseE. Emerging concepts of miRNA therapeutics: From cells to clinic.Trends Genet.202238661362610.1016/j.tig.2022.02.006 35303998
     [Google Scholar]
  204. AbidinS.Z. Mat PauziN.A. MansorN.I. Mohd IsaN.I. HamidA.A. A new perspective on alzheimer’s disease: microRNAs and circular RNAs.Front. Genet.202314123148610.3389/fgene.2023.1231486 37790702
     [Google Scholar]
  205. GongG. AnF. WangY. BianM. YuL.J. WeiC. miR-15b represses BACE1 expression in sporadic alzheimer’s disease.Oncotarget2017853915519155710.18632/oncotarget.21177 29207665
     [Google Scholar]
  206. GabrM.T. BrogiS. MicroRNA-based multitarget approach for alzheimer’s disease: Discovery of the first-in-class dual inhibitor of Acetylcholinesterase and MicroRNA-15b biogenesis.J. Med. Chem.202063179695970410.1021/acs.jmedchem.0c00756 32787143
     [Google Scholar]
  207. PapaA. CursaroI. PozzettiL. ContriC. CappelloM. PasquiniS. CarulloG. RamunnoA. GemmaS. VaraniK. ButiniS. CampianiG. VincenziF. Pioneering first‐in‐class FAAH‐HDAC inhibitors as potential multitarget neuroprotective agents.Arch. Pharm. (Weinheim)202335612230041010.1002/ardp.202300410 37750286
     [Google Scholar]
  208. BasavarajappaB.S. ShivakumarM. JoshiV. SubbannaS. Endocannabinoid system in neurodegenerative disorders.J. Neurochem.2017142562464810.1111/jnc.14098 28608560
     [Google Scholar]
  209. DurantiA. BeldarrainG. ÁlvarezA. SbrisciaM. CarloniS. BalduiniW. Alonso-AlconadaD. The endocannabinoid system as a target for neuroprotection/neuroregeneration in perinatal hypoxic–ischemic brain injury.Biomedicines20221112810.3390/biomedicines11010028 36672536
     [Google Scholar]
  210. SánchezA.J. García-MerinoA. Neuroprotective agents.Cannabinoids. Clin. Immunol.20121421576710.1016/j.clim.2011.02.010 21420365
     [Google Scholar]
  211. ZhuS. ZhangT. ZhengL. LiuH. SongW. LiuD. LiZ. PanC. Combination strategies to maximize the benefits of cancer immunotherapy.J. Hematol. Oncol.202114115610.1186/s13045‑021‑01164‑5 34579759
     [Google Scholar]
  212. PonomarevA.V. ShubinaI.Z. Insights into mechanisms of tumor and immune system interaction: Association with wound healing.Front. Oncol.20199111510.3389/fonc.2019.01115 31709183
     [Google Scholar]
  213. HuoJ.L. WangY.T. FuW.J. LuN. LiuZ.S. The promising immune checkpoint LAG-3 in cancer immunotherapy: From basic research to clinical application.Front. Immunol.20221395609010.3389/fimmu.2022.956090 35958563
     [Google Scholar]
  214. DuttaS. GangulyA. ChatterjeeK. SpadaS. MukherjeeS. Targets of immune escape mechanisms in cancer: Basis for development and evolution of cancer immune checkpoint inhibitors.Biology (Basel)202312221810.3390/biology12020218 36829496
     [Google Scholar]
  215. BasudanA.M. The role of immune checkpoint inhibitors in cancer therapy.Clin. Pract.2022131224010.3390/clinpract13010003 36648843
     [Google Scholar]
  216. BashashD. ZandiZ. KashaniB. Pourbagheri-SigaroodiA. SalariS. GhaffariS.H. Resistance to immunotherapy in human malignancies: Mechanisms, research progresses, challenges, and opportunities.J. Cell. Physiol.2022237134637210.1002/jcp.30575 34498289
     [Google Scholar]
  217. DąbrowskaA. GrubbaM. BalihodzicA. SzotO. SobockiB.K. PerdyanA. The role of regulatory T cells in cancer treatment resistance.Int. J. Mol. Sci.202324181411410.3390/ijms241814114 37762416
     [Google Scholar]
  218. ParabA. Kumar BhattL. OmriA. Targeting epigenetic mechanisms: A boon for cancer immunotherapy.Biomedicines202311116910.3390/biomedicines11010169 36672677
     [Google Scholar]
  219. WangS. WangJ. ChenZ. LuoJ. GuoW. SunL. LinL. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance.NPJ Precis. Oncol.2024813110.1038/s41698‑024‑00522‑z 38341519
     [Google Scholar]
  220. LodewijkI. NunesS.P. HenriqueR. JerónimoC. DueñasM. ParamioJ.M. Tackling tumor microenvironment through epigenetic tools to improve cancer immunotherapy.Clin. Epigenetics20211316310.1186/s13148‑021‑01046‑0 33761971
     [Google Scholar]
  221. WaightJ.D. TakaiS. MarelliB. QinG. HanceK.W. ZhangD. TigheR. LanY. LoK.M. SabzevariH. HofmeisterR. WilsonN.S. Cutting edge: Epigenetic regulation of Foxp3 defines a stable population of CD4+ regulatory T cells in tumors from mice and humans.J. Immunol.2015194387888210.4049/jimmunol.1402725 25548231
     [Google Scholar]
  222. WangD. QuirosJ. MahuronK. PaiC.C. RanzaniV. YoungA. SilveriaS. HarwinT. AbnousianA. PaganiM. RosenblumM.D. Van GoolF. FongL. BluestoneJ.A. DuPageM. Targeting EZH2 reprograms intratumoral regulatory T cells to enhance cancer immunity.Cell Rep.201823113262327410.1016/j.celrep.2018.05.050 29898397
     [Google Scholar]
  223. MantovaniA. MarchesiF. MalesciA. LaghiL. AllavenaP. Tumour-associated macrophages as treatment targets in oncology.Nat. Rev. Clin. Oncol.201714739941610.1038/nrclinonc.2016.217 28117416
     [Google Scholar]
  224. HashimotoA. FukumotoT. ZhangR. GabrilovichD. Selective targeting of different populations of myeloid-derived suppressor cells by histone deacetylase inhibitors.Cancer Immunol. Immunother.20206991929193610.1007/s00262‑020‑02588‑7 32435850
     [Google Scholar]
  225. WangH.F. NingF. LiuZ.C. WuL. LiZ.Q. QiY.F. ZhangG. WangH.S. CaiS.H. DuJ. Histone deacetylase inhibitors deplete myeloid-derived suppressor cells induced by 4T1 mammary tumors in vivo and in vitro.Cancer Immunol. Immunother.201766335536610.1007/s00262‑016‑1935‑1 27915371
     [Google Scholar]
  226. CuiY. CaiJ. WangW. WangS. Regulatory effects of histone deacetylase inhibitors on myeloid-derived suppressor cells.Front. Immunol.20211269020710.3389/fimmu.2021.690207 34149732
     [Google Scholar]
  227. DraghiciuO. LubbersJ. NijmanH.W. DaemenT. Myeloid derived suppressor cells—An overview of combat strategies to increase immunotherapy efficacy.OncoImmunology201541e95482910.4161/21624011.2014.954829 25949858
     [Google Scholar]
  228. DuanZ. LuoY. Targeting macrophages in cancer immunotherapy.Signal Transduct. Target. Ther.20216112710.1038/s41392‑021‑00506‑6 33767177
     [Google Scholar]
  229. NiuY. ChenJ. QiaoY. Epigenetic modifications in tumor-associated macrophages: A new perspective for an old foe.Front. Immunol.20221383622310.3389/fimmu.2022.836223 35140725
     [Google Scholar]
  230. GomezS. TabernackiT. KobyraJ. RobertsP. ChiappinelliK.B. Combining epigenetic and immune therapy to overcome cancer resistance.Semin. Cancer Biol.2020659911310.1016/j.semcancer.2019.12.019 31877341
     [Google Scholar]
  231. GuoR. LiJ. HuJ. FuQ. YanY. XuS. WangX. JiaoF. Combination of epidrugs with immune checkpoint inhibitors in cancer immunotherapy: From theory to therapy.Int. Immunopharmacol.202312011041710.1016/j.intimp.2023.110417 37276826
     [Google Scholar]
  232. WoodsD.M. SodréA.L. VillagraA. SarnaikA. SotomayorE.M. WeberJ. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade.Cancer Immunol. Res.20153121375138510.1158/2326‑6066.CIR‑15‑0077‑T 26297712
     [Google Scholar]
  233. PengD. KryczekI. NagarshethN. ZhaoL. WeiS. WangW. SunY. ZhaoE. VatanL. SzeligaW. KotarskiJ. TarkowskiR. DouY. ChoK. Hensley-AlfordS. MunkarahA. LiuR. ZouW. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy.Nature2015527757724925310.1038/nature15520 26503055
     [Google Scholar]
  234. MazzoneR. ZwergelC. MaiA. ValenteS. Epi-drugs in combination with immunotherapy: A new avenue to improve anticancer efficacy.Clin. Epigenetics2017915910.1186/s13148‑017‑0358‑y 28572863
     [Google Scholar]
  235. DuruisseauxM. EstellerM. Lung cancer epigenetics: From knowledge to applications.Semin. Cancer Biol.20185111612810.1016/j.semcancer.2017.09.005 28919484
     [Google Scholar]
  236. Di GiacomoA.M. CovreA. FinotelloF. RiederD. DanielliR. SigalottiL. GiannarelliD. PetitprezF. LacroixL. ValenteM. CutaiaO. FazioC. AmatoG. LazzeriA. MonterisiS. MiraccoC. CoralS. AnichiniA. BockC. NemcA. OganesianA. LowderJ. AzabM. FridmanW.H. Sautès-FridmanC. TrajanoskiZ. MaioM. Guadecitabine plus ipilimumab in unresectable melanoma: The NIBIT-M4 clinical trial.Clin. Cancer Res.201925247351736210.1158/1078‑0432.CCR‑19‑1335 31530631
     [Google Scholar]
  237. DhimanA. SharmaR. SinghR.K. Target-based anticancer indole derivatives and insight into structure‒activity relationship: A mechanistic review update (2018–2021).Acta Pharm. Sin. B20221273006302710.1016/j.apsb.2022.03.021 35865090
     [Google Scholar]
  238. KumariA. SinghR.K. Medicinal chemistry of indole derivatives: Current to future therapeutic prospectives.Bioorg. Chem.20198910302110.1016/j.bioorg.2019.103021 31176854
     [Google Scholar]
  239. KumariA. SinghR.K. Morpholine as ubiquitous pharmacophore in medicinal chemistry: Deep insight into the structure-activity relationship (SAR).Bioorg. Chem.20209610357810.1016/j.bioorg.2020.103578 31978684
     [Google Scholar]
  240. SinghR.K. KumarS. PrasadD.N. BhardwajT.R. Therapeutic journery of nitrogen mustard as alkylating anticancer agents: Historic to future perspectives.Eur. J. Med. Chem.201815140143310.1016/j.ejmech.2018.04.001 29649739
     [Google Scholar]
  241. SethiN.S. PrasadD.N. SinghR.K. Synthesis, anticancer, and antibacterial studies of benzylidene bearing 5-substituted and 3, 5-disubstituted-2, 4-thiazolidinedione derivatives.Med. Chem.202117436937910.2174/1573406416666200512073640 32394843
     [Google Scholar]
/content/journals/ctmc/10.2174/0115680266337668241025061804
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Computer-aided Drug Discovery of Epigenetic Modulators in Dual-target Therapy of Multifactorial Diseases
Curr. Top. Med. Chem. 25, 1907 (2025); https://doi.org/10.2174/0115680266337668241025061804
/content/journals/ctmc/10.2174/0115680266337668241025061804
/content/journals/ctmc/10.2174/0115680266337668241025061804
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  • Article Type:     Review Article
Keyword(s): chemoinformatic; Computer-aided drug design (CADD); dual-target inhibitors; epigenetic inhibitors; multi-factorial diseases; neurodegeneration

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