Skip to content
2000
Volume 21, Issue 5
  • ISSN: 1573-4099
  • E-ISSN: 1875-6697

Abstract

Objectives

Cancer poses a great threat to human health, and effective drugs to treat it are always needed. Several compounds containing a 2-aminopyrazine framework have been identified as antitumor agents with SHP2 inhibition activities. This current work aimed to search for more potent novel compounds possessing a 2-aminopyrazine moiety with antitumor activities.

Methods

A series of 12 novel 2-aminopyrazine derivatives was synthesized, and their structures were confirmed by spectroscopic techniques. The inhibitory activities of all the synthesized compounds against MDA-MB-231 and H1975 cancer cell lines were evaluated by an MTT assay. The most potent compound was analyzed by flow cytometry. Subsequently, computational studies were performed to investigate the possible antitumor mechanisms of compound .

Results

The results indicated that compound exhibited potent antitumor activities with IC values of 11.84 ± 0.83 μM against H1975 cells and 5.66 ± 2.39 μM against MDA-MB-231 cells, which were more potent than the SHP2 inhibitor GS493 (IC = 19.08 ± 1.01 μM against H1975 cells and IC = 25.02 ± 1.47 μM against MDA-MB-231 cells). Further analysis by flow cytometry demonstrated that compound induced cell apoptosis in H1975 cells. The results of the molecular docking and MD simulations, including RMSD, RMSF, PCA, DCCM and binding energy and decomposition analyses, revealed that compound probably selectively inhibited SHP2.

Conclusion

A new compound having a 2-aminopyrazine substructure with potent inhibitory activities against the H1975 and MDA-MB-231 cancer cells was obtained, meriting further investigation as an antitumor drug.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cad/10.2174/0115734099285448240304072649
2024-03-12
2025-10-17

  • From This Site

    /content/journals/cad/10.2174/0115734099285448240304072649
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. LinS. MalkaniS. LombardoM. YangL. MillsS.G. ChapmanK. ThompsonJ.E. ZhangW.X. WangR. CubbonR.M. O’NeillE.A. HaleJ.J. Design, synthesis, and biological evaluation of aminopyrazine derivatives as inhibitors of mitogen-activated protein kinase-activated protein kinase 2 (MK-2).Bioorg. Med. Chem. Lett.201525225402540810.1016/j.bmcl.2015.09.01626403928
     [Google Scholar]
  2. FuY. TangS. SuY. LanX. YeY. ZhaC. LiL. CaoJ. ChenY. JiangL. HuangY. DingJ. GengM. HuangM. WanH. Discovery of a class of diheteroaromatic amines as orally bioavailable CDK1/4/6 inhibitors.Bioorg. Med. Chem. Lett.201727235332533610.1016/j.bmcl.2017.09.05029074254
     [Google Scholar]
  3. ChughA. KumarA. VermaA. KumarS. KumarP. A review of antimalarial activity of two or three nitrogen atoms containing heterocyclic compounds.Med. Chem. Res.202029101723175010.1007/s00044‑020‑02604‑6
     [Google Scholar]
  4. SongY. WangS. ZhaoM. YangX. YuB. Strategies targeting protein tyrosine phosphatase SHP2 for cancer therapy.J. Med. Chem.20226543066307910.1021/acs.jmedchem.1c0200835157464
     [Google Scholar]
  5. YuanX. BuH. ZhouJ. YangC.Y. ZhangH. Recent advances of SHP2 inhibitors in cancer therapy: Current development and clinical application.J. Med. Chem.20206320113681139610.1021/acs.jmedchem.0c0024932460492
     [Google Scholar]
  6. PetrocchiA. GrilloA. FerranteL. RandazzoP. PrandiA. De MatteoM. IaccarinoC. BisbocciM. CellucciA. AlliC. NibbioM. PucciV. AmaudrutJ. MontalbettiC. ToniattiC. FabioD.R. Discovery of a novel seriesof potent SHP2 allosteric inhibitors.ACS Med. Chem. Lett.202314564565110.1021/acsmedchemlett.3c0005937197453
     [Google Scholar]
  7. YangX. XiongJ. YuB. SongY. Emerging therapeutic approaches of SHP2-targeted modulators.Future Med. Chem.202416429129410.4155/fmc‑2023‑034838275153
     [Google Scholar]
  8. ChenC. ChengY. LeiH. FengX. ZhangH. QiL. WanJ. XuH. ZhaoX. ZhangY. YangB. SHP2 potentiates anti-PD-1 effectiveness through intervening cell pyroptosis resistance in triple-negative breast cancer.Biomed. Pharmacother.202316811579710.1016/j.biopha.2023.11579737913735
     [Google Scholar]
  9. KongJ. LongY.Q. Recent advances in the discovery of protein tyrosine phosphatase SHP2 inhibitors.RSC Med. Chem.202213324625710.1039/D1MD00386K35434626
     [Google Scholar]
  10. TangK. ZhaoM. WuY.H. WuQ. WangS. DongY. YuB. SongY. LiuH.M. Structure-based design, synthesis and biological evaluation of aminopyrazines as highly potent, selective, and cellularly active allosteric SHP2 inhibitors.Eur. J. Med. Chem.202223011410610.1016/j.ejmech.2022.11410635063735
     [Google Scholar]
  11. SodirN.M. PathriaG. AdamkewiczJ.I. KelleyE.H. SudhamsuJ. MerchantM. ChiarleR. MaddaloD. SHP2: A pleiotropic target at the interface of cancer and its microenvironment.Cancer Discov.202313112339235510.1158/2159‑8290.CD‑23‑038337682219
     [Google Scholar]
  12. PonziS. FerrignoF. BisbocciM. AlliC. OntoriaJ.M. PetrocchiA. ToniattiC. TorrenteE. Direct-to-biology platform: From synthesis to biological evaluation of SHP2 allosteric inhibitors.Bioorg. Med. Chem. Lett.202410012962610.1016/j.bmcl.2024.12962638266789
     [Google Scholar]
  13. GrosskopfS. EckertC. ArkonaC. RadetzkiS. BöhmK. HeinemannU. WolberG. von KriesJ.P. BirchmeierW. RademannJ. Selective inhibitors of the protein tyrosine phosphatase SHP2 block cellular motility and growth of cancer cells in vitro and in vivo.ChemMedChem201510581582610.1002/cmdc.20150001525877780
     [Google Scholar]
  14. HuX. CuiZ. DongW. ZhuY. GaoC. XuS. YuanQ. YuZ. MinZ. Synthesis and antitumor activity of novel phenylhydrazonopyrazolone derivatives and molecular dynamics simulations.Res. Chem. Intermed.20184495107512210.1007/s11164‑018‑3412‑2
     [Google Scholar]
  15. LadeD.M. NicolettiR. MerschJ. AgazieY.M. Design and synthesis of improved active-site SHP2 inhibitors with anti-breast cancer cell effects.Eur. J. Med. Chem.202324711501710.1016/j.ejmech.2022.11501736584630
     [Google Scholar]
  16. SalamounJ.M. WipfP. Allosteric modulation of phosphatase activity may redefinetherapeutic value.J. Med. Chem.201659177771777210.1021/acs.jmedchem.6b0121027539118
     [Google Scholar]
  17. Garcia FortanetJ. ChenC.H.T. ChenY.N.P. ChenZ. DengZ. FirestoneB. FekkesP. FodorM. FortinP.D. FridrichC. GrunenfelderD. HoS. KangZ.B. KarkiR. KatoM. KeenN. LaBonteL.R. LarrowJ. LenoirF. LiuG. LiuS. LombardoF. MajumdarD. MeyerM.J. PalermoM. PerezL. PuM. RamseyT. SellersW.R. ShultzM.D. StamsT. TowlerC. WangP. WilliamsS.L. ZhangJ.H. LaMarcheM.J. Allosteric inhibition of SHP2:Identification of a potent, selective, and orally efficacious phosphataseinhibitor.J. Med. Chem.201659177773778210.1021/acs.jmedchem.6b0068027347692
     [Google Scholar]
  18. HouQ. JiangW. LiW. HuangC. YangK. ChenX. HuangM. ShuC. LuoG. SunH. ChuQ. WuX. Identification of a novel, potent, and orally bioavailable guanidine-based SHP2 allosteric inhibitor from virtual screening and rational structural optimization for the treatment of KRAS mutant cancers.J. Med. Chem.20236619136461366410.1021/acs.jmedchem.3c0099237754066
     [Google Scholar]
  19. ElsayedM.S.A. BlakeJ.F. BoysM.L. BrownE. ChapsalB.D. ChicarelliM.J. CookA.W. FellJ.B. FischerJ.P. HansonL. LemieuxC. MartinsonM.C. McCownJ. McNultyO.T. MejiaM.J. NeitzelN.A. OttenJ.N. RodriguezM.E. WilcoxD. WongC.E. ZhouY. HinklinR.J. Discovery of 5-azaquinoxaline derivatives as potent and orally bioavailable allosteric SHP2 inhibitors.ACS Med. Chem. Lett.202314121673168110.1021/acsmedchemlett.3c0031038116446
     [Google Scholar]
  20. WangN. ZhuS. LvD. WangY. KhawarM.B. SunH. Allosteric modulation of SHP2: Quest from known to unknown.Drug Dev. Res.20238471395141010.1002/ddr.2210037583266
     [Google Scholar]
  21. LiuW.S. ZhaoJ.F. GuoX.J. LuS.Z. LiW. LiW.Z. Design, synthesis, activity and molecular dynamics studies of 1,3,4-thiadiazole derivatives as selective allosteric inhibitors of SHP2 for the treatment of cancer.Eur. J. Med. Chem.202325811558510.1016/j.ejmech.2023.11558537390510
     [Google Scholar]
  22. LuS. QiuY. NiD. HeX. PuJ. ZhangJ. Emergence of allosteric drug-resistance mutations: New challenges for allosteric drug discovery.Drug Discov. Today202025117718410.1016/j.drudis.2019.10.00631634592
     [Google Scholar]
  23. LaRochelleJ.R. FodorM. VemulapalliV. MohseniM. WangP. StamsT. LaMarcheM.J. ChopraR. AckerM.G. BlacklowS.C. Structural reorganization of SHP2 by oncogenic mutations and implications for oncoprotein resistance to allosteric inhibition.Nat. Commun.201891450810.1038/s41467‑018‑06823‑930375388
     [Google Scholar]
  24. ChenY.N.P. LaMarcheM.J. ChanH.M. FekkesP. Garcia-FortanetJ. AckerM.G. AntonakosB. ChenC.H.T. ChenZ. CookeV.G. DobsonJ.R. DengZ. FeiF. FirestoneB. FodorM. FridrichC. GaoH. GrunenfelderD. HaoH.X. JacobJ. HoS. HsiaoK. KangZ.B. KarkiR. KatoM. LarrowJ. La BonteL.R. LenoirF. LiuG. LiuS. MajumdarD. MeyerM.J. PalermoM. PerezL. PuM. PriceE. QuinnC. ShakyaS. ShultzM.D. SliszJ. VenkatesanK. WangP. WarmuthM. WilliamsS. YangG. YuanJ. ZhangJ.H. ZhuP. RamseyT. KeenN.J. SellersW.R. StamsT. FortinP.D. Allosteric inhibition of SHP2 phosphatase inhibits cancers driven by receptor tyrosine kinases.Nature2016535761014815210.1038/nature1862127362227
     [Google Scholar]
  25. YangchunM. WenYuY. LiangZ. LiPengL. JingWeiW. WeiYaL. ShanD. YingM. RunLingW. Exploring the cause of the dual allosteric targeted inhibition attaching to allosteric sites enhancing SHP2 inhibition.Mol. Divers.20222631567158010.1007/s11030‑021‑10286‑434338914
     [Google Scholar]
  26. TorrenteE. FodaleV. CiammaichellaA. FerrignoF. OntoriaJ.M. PonziS. RossettiI. SferrazzaA. AmaudrutJ. MissineoA. EspositoS. PalomboS. NibbioM. CerretaniM. BisbocciM. CellucciA. di MarcoA. AlliC. PucciV. ToniattiC. PetrocchiA. Discovery of a novel series of imidazopyrazine derivatives as potent SHP2 allosteric inhibitors.ACS Med. Chem. Lett.202314215616210.1021/acsmedchemlett.2c0045436793438
     [Google Scholar]
  27. TrottO. OlsonA.J. AutoDock vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.2133419499576
     [Google Scholar]
  28. AbrahamM.J. MurtolaT. SchulzR. PállS. SmithJ.C. HessB. LindahlE. GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers.SoftwareX20151-2192510.1016/j.softx.2015.06.001
     [Google Scholar]
  29. CeruttiD.S. DukeR.E. DardenT.A. LybrandT.P. Staggered mesh ewald: An extension of the smooth particle-mesh ewald method adding great versatility.J. Chem. Theory Comput.2009592322233810.1021/ct900101520174456
     [Google Scholar]
  30. HessB. P-LINCS: A parallel linear constraint solver for molecular simulation.J. Chem. Theory Comput.20084111612210.1021/ct700200b26619985
     [Google Scholar]
  31. KumariR. KumarR. LynnA. g_mmpbsa--a GROMACS tool for high-throughput MM-PBSA calculations.J. Chem. Inf. Model.20145471951196210.1021/ci500020m24850022
     [Google Scholar]
  32. CarvalhoH.F. BarbosaA.J.M. RoqueA.C.A. IranzoO. BrancoR.J.F. Integration of molecular dynamics based predictions into theoptimization of de novo protein designs: Limitations and benefits.Methods Mol. Biol.2017152918120110.1007/978‑1‑4939‑6637‑0_827914051
     [Google Scholar]
  33. CamposM.R.S. del BojórquezC.Q.N. Traditional and novel computer-aided drug design (CADD) approaches in the anticancer drug discovery process.Curr. Cancer Drug Targets202323533334510.2174/156800962266622070510424935792126
     [Google Scholar]
  34. KaramanB. SipplW. Computational drug repurposing: Current trends.Curr. Med. Chem.201926285389540910.2174/092986732566618053010033229848268
     [Google Scholar]
  35. MaliS.N. PandeyA. Synthesis, computational analysis, antimicrobial, antioxidant, trypan blue exclusion assay, β-hematin assay and anti-inflammatory studies of some hydrazones (Part-I). Curr. Comput. Aided. Curr. Computeraided Drug Des.202319210812210.2174/157340991866622092914582436177631
     [Google Scholar]
  36. BansalR. SinghR. RanaP. Synthesis, in silico studies and pharmacological evaluation of a new series of indanone derivatives as anti-Parkinsonian and anti-Alzheimer’s agents.Curr. Computeraided Drug Des.20231929410710.2174/157340991966622112915511036453500
     [Google Scholar]
  37. LuoR. FuW. ShaoJ. MaL. ShuaiS. XuY. JiangZ. YeZ. ZhengL. ZhengL. YuJ. ZhangY. YinL. TuL. LvX. LiJ. LiangG. ChenL. Discovery of a potent and selective allosteric inhibitor targeting the SHP2 tunnel site for RTK-driven cancer treatment.Eur. J. Med. Chem.202325311530510.1016/j.ejmech.2023.11530537023678
     [Google Scholar]
  38. VazhappillyC.G. SalehE. RamadanW. MenonV. Al-AzawiA.M. TaraziH. AllahA.H. ShorbagiE.A.N. AwadyE.R. Inhibition of SHP2 by new compounds induces differential effects on RAS/RAF/ERK and PI3K/AKT pathways in different cancer cell types.Invest. New Drugs201937225226110.1007/s10637‑018‑0626‑529947013
     [Google Scholar]
  39. LadeD.M. AgazieY.M. Targeting SHP2 with an active site inhibitor blocks signaling and breast cancer cell phenotypes.ACS. Bio. Med. Chem. Au.202335418428
     [Google Scholar]
  40. BundaS. BurrellK. HeirP. ZengL. AlamsahebpourA. KanoY. RaughtB. ZhangZ.Y. ZadehG. OhhM. Inhibition of SHP2-mediated dephosphorylation of Ras suppresses oncogenesis.Nat. Commun.201561885910.1038/ncomms985926617336
     [Google Scholar]
  41. LarssonP. KneiszlR.C. MarklundE.G. MkVsites : A tool for creating GROMACS virtual sites parameters to increase performance in all‐atom molecular dynamics simulations.J. Comput. Chem.202041161564156910.1002/jcc.2619832282082
     [Google Scholar]
  42. SinghE. JhaR.K. KhanR.J. KumarA. JainM. MuthukumaranJ. SinghA.K. A computational essential dynamics approach to investigate structural influences of ligand binding on Papain like protease from SARS-CoV-2.Comput. Biol. Chem.20229910772110.1016/j.compbiolchem.2022.10772135835027
     [Google Scholar]
  43. KumariP. PoddarR. A comparative multivariate analysis of nitrilase enzymes: An ensemble based computational approach.Comput. Biol. Chem.20198310709510.1016/j.compbiolchem.2019.10709531442709
     [Google Scholar]
  44. KhanA. LiW. AmbreenA. WeiD.Q. WangY. MaoY. A protein coupling and molecular simulation analysis of the clinical mutants of androgen receptor revealed a higher binding for Leupaxin, to increase the prostate cancer invasion and motility.Comput. Biol. Med.202214610553710.1016/j.compbiomed.2022.10553735504219
     [Google Scholar]
  45. ZhouL. FengY. MaY.C. ZhangZ. WuJ.W. DuS. LiW.Y. LuX.H. MaY. WangR.L. Exploring the mechanism of the potent allosteric inhibitor compound2 on SHP2 WT and SHP2F285S by molecular dynamics study.J. Mol. Graph. Model.202110310780710.1016/j.jmgm.2020.10780733338846
     [Google Scholar]
  46. TakemuraK. MatubayasiN. KitaoA. Binding free energy analysis of protein-protein docking model structures by evERdock.J. Chem. Phys.20181481010510110.1063/1.501986429544320
     [Google Scholar]
  47. SittelF. JainA. StockG. Principal component analysis of molecular dynamics: On the use of Cartesian vs. internal coordinates.J. Chem. Phys.2014141101411110.1063/1.488533825005281
     [Google Scholar]
  48. SureshP.S. KesarwaniV. KumariS. ShankarR. SharmaU. Bisbenzylisoquinolines from Cissampelos pareira L. as antimalarial agents: Molecular docking, pharmacokinetics analysis, and molecular dynamic simulation studies.Comput. Biol. Chem.202310410782610.1016/j.compbiolchem.2023.10782636848855
     [Google Scholar]
  49. KormosB.L. BarangerA.M. BeveridgeD.L. Do collective atomic fluctuations account for cooperative effects? Molecular dynamics studies of the U1A-RNA complex.J. Am. Chem. Soc.2006128288992899310.1021/ja060607116834346
     [Google Scholar]
  50. NdagiU. MhlongoN.N. SolimanM.E. The impact of Thr91 mutation on c-Src resistance to UM-164: Molecular dynamics study revealed a new opportunity for drug design.Mol. Biosyst.20171361157117110.1039/C6MB00848H28463369
     [Google Scholar]
  51. YuH. DalbyP.A. Coupled molecular dynamics mediate long- and short-range epistasis between mutations that affect stability and aggregation kinetics.Proc. Natl. Acad. Sci.201811547E11043E1105210.1073/pnas.181032411530404916
     [Google Scholar]
/content/journals/cad/10.2174/0115734099285448240304072649
Loading
Design, Synthesis, Antitumor Activity Evaluation, and Molecular Dynamics Simulation of Some 2-aminopyrazine Derivatives
Curr. Computeraided Drug Des. 21, 639 (2025); https://doi.org/10.2174/0115734099285448240304072649
/content/journals/cad/10.2174/0115734099285448240304072649
/content/journals/cad/10.2174/0115734099285448240304072649
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keyword(s): 2-Aminopyrazine; antitumor; molecular docking; molecular dynamics simulation; SHP2 inhibitor; synthesis

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test