Skip to content
2000
Volume 32, Issue 40
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X
file format text download EPUB
file format pdf download PDF
side by side viewer icon HTML

Abstract

The KRAS protein is one of the key targets in cancer therapy. The clinical application of covalent KRAS inhibitors (sotorasib, adagrasib) is limited to the treatment of only certain KRASG12C-mediated types of cancer. In addition, using covalent inhibitors has several drawbacks, the main ones being limited to specific mutations (, G12C) and the potential development of mutagenic resistance in tumors. Recently, the first representatives of a new class of allosteric inhibitors, termed pan-KRAS, have been discovered and studied due to their activity against multiple mutant forms of the KRAS protein. The development of pan-KRAS inhibitors represents a promising new direction in the therapeutic approach to treating KRAS-mediated cancers. The possibility to target multiple mutant forms of KRAS will significantly enlarge the number of patients that benefit from the therapy and reduce the likelihood of mutagenic resistance in tumors. This study reviews patents published between 2022 and 2024 that present new pan-specific KRAS inhibitors. The consideration of 28 patents included descriptions of the structures of the presented molecules, identification of the most active and selective examples of compounds, as well as results from structure-activity relationship (SAR) analyses for each sample. As a result of this work, some structural features of the most active examples of pan-KRAS inhibitors were identified.

© 2025 The Author(s). Published by Bentham Science Publishers.
This is an open access article published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673372217250515031136
2025-06-13
2025-12-05

  • From This Site

    /content/journals/cmc/10.2174/0109298673372217250515031136
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

/deliver/fulltext/cmc/32/40/CMC-32-40-09.html?itemId=/content/journals/cmc/10.2174/0109298673372217250515031136&mimeType=html&fmt=ahah

References

  1. MphR.L.S. DvmA. J. Cancer statistics, 2024.CA Cancer J. Clin.2024741124910.3322/caac.21820 38230766
     [Google Scholar]
  2. DeVitaV.T.Jr ChuE. A history of cancer chemotherapy.Cancer Res.200868218643865310.1158/0008‑5472.CAN‑07‑6611 18974103
     [Google Scholar]
  3. ChabnerB.A. RobertsT.G. Jr. Chemotherapy and the war on cancer.Nat. Rev. Cancer200551657210.1038/nrc1529 15630416
     [Google Scholar]
  4. DevitaV.T.Jr SerpickA.A. CarboneP.P. Combination chemotherapy in the treatment of advanced Hodgkin’s disease.Ann. Intern. Med.197073688189510.7326/0003‑4819‑73‑6‑881 5525541
     [Google Scholar]
  5. ConnorsJ.M. State-of-the-art therapeutics: Hodgkin’s lymphoma.J. Clin. Oncol.200523266400640810.1200/JCO.2005.05.016 16155026
     [Google Scholar]
  6. DrukerB.J. TalpazM. RestaD.J. PengB. BuchdungerE. FordJ.M. LydonN.B. KantarjianH. CapdevilleR. Ohno-JonesS. SawyersC.L. Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.N. Engl. J. Med.2001344141031103710.1056/NEJM200104053441401 11287972
     [Google Scholar]
  7. SlamonD.J. Leyland-JonesB. ShakS. FuchsH. PatonV. BajamondeA. FlemingT. EiermannW. WolterJ. PegramM. BaselgaJ. NortonL. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N. Engl. J. Med.20013441178379210.1056/NEJM200103153441101 11248153
     [Google Scholar]
  8. HudisC.A. Trastuzumab--Mechanism of action and use in clinical practice.N. Engl. J. Med.20073571395110.1056/NEJMra043186 17611206
     [Google Scholar]
  9. GarrawayL.A. JänneP.A. Circumventing cancer drug resistance in the era of personalized medicine.Cancer Discov.20122321422610.1158/2159‑8290.CD‑12‑0012 22585993
     [Google Scholar]
  10. DienstmannR. RodonJ. BarretinaJ. TaberneroJ. Genomic medicine frontier in human solid tumors: Prospects and challenges.J. Clin. Oncol.201331151874188410.1200/JCO.2012.45.2268 23589551
     [Google Scholar]
  11. SonkinD. ThomasA. TeicherB.A. Cancer treatments: Past, present, and future.Cancer Genet.2024286-287March182410.1016/j.cancergen.2024.06.002 38909530
     [Google Scholar]
  12. SimanshuD.K. NissleyD.V. McCormickF. RAS proteins and their regulators in human disease.Cell20171701173310.1016/j.cell.2017.06.009 28666118
     [Google Scholar]
  13. Fernández-medardeA. SantosE. Ras in cancer and developmental diseases.Genes Cancer20112334435810.1177/1947601911411084 21779504
     [Google Scholar]
  14. BaharE. KimH.J. KimD.R. Targeting the RAS/RAF/MAPK pathway for cancer therapy: From mechanism to clinical studies.Signal Transduct. Target. Ther.20238145510.1038/s41392‑023‑01705‑z 38105263
     [Google Scholar]
  15. FatimaS. PansuriyaN. LakhaniA. MadhuriS. AjmalR. ClementinaR. LakdawalaZ. ShahK. DilshanaH. AndreaM. MathewB. RahejaA. KRAS as a prognostic and predictive marker in metastatic non-small cell lung carcinoma: A systematic review.Cureus2024165e6006110.7759/cureus.60061 38860089
     [Google Scholar]
  16. ZerA. DingK. LeeS.M. GossG.D. SeymourL. EllisP.M. HackshawA. BradburyP.A. HanL. O’CallaghanC.J. TsaoM.S. ShepherdF.A. Pooled analysis of the prognostic and predictive value of KRAS mutation status and mutation subtype in patients with non-small cell lung cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors.J. Thorac. Oncol.201611331232310.1016/j.jtho.2015.11.010 26749487
     [Google Scholar]
  17. LinardouH. DahabrehI.J. KanaloupitiD. SiannisF. BafaloukosD. KosmidisP. PapadimitriouC.A. MurrayS. Assessment of somatic k-RAS mutations as a mechanism associated with resistance to EGFR-targeted agents: A systematic review and meta-analysis of studies in advanced non-small-cell lung cancer and metastatic colorectal cancer.Lancet Oncol.200891096297210.1016/S1470‑2045(08)70206‑7 18804418
     [Google Scholar]
  18. MaoC. QiuL.X. LiaoR.Y. DuF.B. DingH. YangW.C. LiJ. ChenQ. KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: A meta-analysis of 22 studies.Lung Cancer201069327227810.1016/j.lungcan.2009.11.020 20022659
     [Google Scholar]
  19. ManolakosP. WardL.D. A critical review of the prognostic and predictive implications of KRAS and STK11 mutations and co-mutations in metastatic non-small lung cancer.J. Pers. Med.2023136101010.3390/jpm13061010 37373999
     [Google Scholar]
  20. CotanH.T. EmilescuR.A. IaciuC.I. Orlov-slavuC.M. OlaruM.C. PopaA.M. JingaM. NitipirC. SchreinerO.D. CiobanuR.C. Prognostic and predictive determinants of colorectal cancer: A comprehensive review.Cancers20241623392810.3390/cancers16233928 39682117
     [Google Scholar]
  21. PaoW. WangT.Y. RielyG.J. MillerV.A. PanQ. LadanyiM. ZakowskiM.F. HeelanR.T. KrisM.G. VarmusH.E. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.PLoS Med.200521e1710.1371/journal.pmed.0020017 15696205
     [Google Scholar]
  22. JänneP.A. ShawA.T. PereiraJ.R. JeanninG. VansteenkisteJ. BarriosC. FrankeF.A. GrinstedL. ZazulinaV. SmithP. SmithI. CrinòL. Selumetinib plus docetaxel for KRAS-mutant advanced non-small-cell lung cancer: A randomised, multicentre, placebo-controlled, phase 2 study.Lancet Oncol.2013141384710.1016/S1470‑2045(12)70489‑8 23200175
     [Google Scholar]
  23. MooreA.R. RosenbergS.C. McCormickF. MalekS. RAS-targeted therapies: Is the undruggable drugged?Nat. Rev. Drug Discov.202019853355210.1038/s41573‑020‑0068‑6 32528145
     [Google Scholar]
  24. LuS. JangH. GuS. ZhangJ. NussinovR. Drugging Ras GTPase: A comprehensive mechanistic and signaling structural view.Chem. Soc. Rev.201645184929495210.1039/C5CS00911A 27396271
     [Google Scholar]
  25. BosJ.L. RehmannH. WittinghoferA. GEFs and GAPs: Critical elements in the control of small G proteins.Cell2007129586587710.1016/j.cell.2007.05.018 17540168
     [Google Scholar]
  26. JankuF. YapT.A. Meric-BernstamF. Targeting the PI3K pathway in cancer: Are we making headway?Nat. Rev. Clin. Oncol.201815527329110.1038/nrclinonc.2018.28 29508857
     [Google Scholar]
  27. DrostenM. BarbacidM. Targeting the MAPK pathway in Kras-driven tumors.Cancer Cell202037454355010.1016/j.ccell.2020.03.013 32289276
     [Google Scholar]
  28. CoxA.D. FesikS.W. KimmelmanA.C. LuoJ. DerC.J. Drugging the undruggable RAS: Mission possible?Nat. Rev. Drug Discov.2014131182885110.1038/nrd4389 25323927
     [Google Scholar]
  29. MüllerM.P. JeganathanS. HeidrichA. CamposJ. GoodyR.S. Nucleotide based covalent inhibitors of KRas can only be efficient in vivo if they bind reversibly with GTP-like affinity.Sci. Rep.201771368710.1038/s41598‑017‑03973‑6 28623374
     [Google Scholar]
  30. SinghJ. PetterR.C. BaillieT.A. WhittyA. The resurgence of covalent drugs.Nat. Rev. Drug Discov.201110430731710.1038/nrd3410 21455239
     [Google Scholar]
  31. CrommP.M. SpiegelJ. GrossmannT.N. WaldmannH. Direct modulation of small GTPase activity and function.Angew. Chem. Int. Ed.20155446135161353710.1002/anie.201504357 26470842
     [Google Scholar]
  32. GrayJ.L. von DelftF. BrennanP.E. Targeting the small GTPase superfamily through their regulatory proteins.Angew. Chem. Int. Ed.202059166342636610.1002/anie.201900585 30869179
     [Google Scholar]
  33. ZhangY. LarraufieM.H. MusaviL. AkkirajuH. BrownL.M. StockwellB.R. Design of small molecules that compete with nucleotide binding to an engineered oncogenic KRAS allele.Biochemistry20185781380138910.1021/acs.biochem.7b01113 29313669
     [Google Scholar]
  34. PatricelliM.P. JanesM.R. LiL.S. HansenR. PetersU. KesslerL.V. ChenY. KucharskiJ.M. FengJ. ElyT. ChenJ.H. FirdausS.J. BabbarA. RenP. LiuY. Selective inhibition of oncogenic Kras output with small molecules targeting the inactive state.Cancer Discov.20166331632910.1158/2159‑8290.CD‑15‑1105 26739882
     [Google Scholar]
  35. LitoP. SolomonM. LiL.S. HansenR. RosenN. Allele-specific inhibitors inactivate mutant KRAS G12C by a trapping mechanism.Science2016351627360460810.1126/science.aad6204 26841430
     [Google Scholar]
  36. KimD. XueJ.Y. LitoP. Targeting Kras(G12C): From inhibitory mechanism to modulation of antitumor effects in patients.Cell2020183485085910.1016/j.cell.2020.09.044 33065029
     [Google Scholar]
  37. JanesM.R. ZhangJ. LiL.S. HansenR. PetersU. GuoX. ChenY. BabbarA. FirdausS.J. DarjaniaL. FengJ. ChenJ.H. LiS. LiS. LongY.O. ThachC. LiuY. ZariehA. ElyT. KucharskiJ.M. KesslerL.V. WuT. YuK. WangY. YaoY. DengX. ZarrinkarP.P. BrehmerD. DhanakD. LorenziM.V. Hu-LoweD. PatricelliM.P. RenP. LiuY. Targeting Kras mutant cancers with a covalent G12C-specific inhibitor.Cell20181723578589.e1710.1016/j.cell.2018.01.006 29373830
     [Google Scholar]
  38. OstremJ.M. PetersU. SosM.L. WellsJ.A. ShokatK.M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.Nature2013503747754855110.1038/nature12796 24256730
     [Google Scholar]
  39. SkoulidisF. LiB.T. DyG.K. PriceT.J. FalchookG.S. WolfJ. ItalianoA. SchulerM. BorghaeiH. BarlesiF. KatoT. Curioni-FontecedroA. SacherA. SpiraA. RamalingamS.S. TakahashiT. BesseB. AndersonA. AngA. TranQ. MatherO. HenaryH. NgarmchamnanrithG. FribergG. VelchetiV. GovindanR. Sotorasib for lung cancers with KRAS p.G12C mutation.N. Engl. J. Med.2021384252371238110.1056/NEJMoa2103695 34096690
     [Google Scholar]
  40. JänneP.A. RielyG.J. GadgeelS.M. HeistR.S. OuS.H.I. PachecoJ.M. JohnsonM.L. SabariJ.K. LeventakosK. YauE. BazhenovaL. NegraoM.V. PennellN.A. ZhangJ. AnderesK. Der-TorossianH. KheohT. VelasteguiK. YanX. ChristensenJ.G. ChaoR.C. SpiraA.I. Adagrasib in non-small-cell lung cancer harboring a KRAS G12C mutation.N. Engl. J. Med.2022387212013110.1056/NEJMoa2204619 35658005
     [Google Scholar]
  41. LiZ. SongZ. ZhaoY. WangP. JiangL. GongY. ZhouJ. JianH. DongX. ZhuangW. CangS. YangN. FangJ. ShiJ. LuJ. MaR. WuP. ZhangY. SongM. XuC.W. ShiZ. ZhangL. WangY. WangX. ZhangY. LuS. D-1553 (Garsorasib), a potent and selective inhibitor of KrasG12C in patients with NSCLC: Phase 1 study results.J. Thorac. Oncol.202318794095110.1016/j.jtho.2023.03.015 36948246
     [Google Scholar]
  42. SacherA. LoRussoP. PatelM.R. MillerW.H.Jr GarraldaE. ForsterM.D. SantoroA. FalconA. KimT.W. Paz-AresL. BowyerS. de MiguelM. HanS.W. KrebsM.G. LeeJ.S. ChengM.L. ArbourK. MassarelliE. ChoiY. ShiZ. MandlekarS. LinM.T. Royer-JooS. ChangJ. DhariaN.V. SchutzmanJ.L. DesaiJ. Single-agent divarasib (GDC-6036) in solid tumors with a Kras G12C mutation.N. Engl. J. Med.2023389871072110.1056/NEJMoa2303810 37611121
     [Google Scholar]
  43. GregorcV. González-CaoM. SalvagniS. KoumarianouA. Gil-BazoI. MaioM. ViteriS. MajemM. GutiérrezV. Bernabe CaroR. SanmamedM.F. ZhuH. ShenH. WangY. RosellR. KROCUS: A phase II study investigating the efficacy and safety of fulzerasib (GFH925) in combination with cetuximab in patients with previously untreated advanced KRAS G12C mutated NSCLC.J. Clin. Oncol.20244217_supplLBA8511LBA851110.1200/JCO.2024.42.17_suppl.LBA8511
     [Google Scholar]
  44. WangJ. ZhaoJ. ZhongJ. LiX. FangJ. YuY. LiX. FangX. ChangJ. LiuZ. ZhaoY. SongQ. BaiC. Wang-GillamA. DingY. RaoZ. BiC. 653O Glecirasib (KRAS G12C inhibitor) in combination with JAB-3312 (SHP2 inhibitor) in patients with KRAS p.G12C mutated solid tumors.Ann. Oncol.202334S45910.1016/j.annonc.2023.09.1839
     [Google Scholar]
  45. FDA grants accelerated approval to sotorasib for KRAS G12C mutated NSCLC.Available from: https://www.fda.gov/drugs/resources-informationapproved-drugs/fda-grants-accelerated-approval-sotorasibkras-g12c-mutated-nsclc 2021
  46. FDA grants accelerated approval to adagrasib for KRAS G12C-mutated NSCLC.Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-adagrasib-kras-g12c-mutated-nsclc#:~:text=On%20December%2012%2C%202022%2C%20the,by%20an%20FDA%2Dapproved%20test%2C 2022
  47. SeraniS. FDA rejects SNDA for sotorasib in Kras G12C-mutated NSCLC, targeted oncology.Available from: Https://Www.Targetedonc.Com/View/Fda-Rejects-Nda-for-Sotorasib-in-Kras-G12c-Mutated-Nsclc 2024
  48. Study of MRTX1133 in patients with advanced solid tumors harboring a Kras G12D mutation.NCT057377062025
     [Google Scholar]
  49. JiX. LiY. KongX. ChenD. LuJ. Discovery of prodrug of MRTX1133 as an oral therapy for cancers with Kras G12D mutation.ACS Omega2023877211722110.1021/acsomega.3c00329 36844555
     [Google Scholar]
  50. KimD. HerdeisL. RudolphD. ZhaoY. BöttcherJ. VidesA. Ayala-SantosC.I. PourfarjamY. Cuevas-NavarroA. XueJ.Y. MantoulidisA. BrökerJ. WunbergT. SchaafO. PopowJ. WolkerstorferB. KropatschK.G. QuR. de StanchinaE. SangB. LiC. McConnellD.B. KrautN. LitoP. Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.Nature2023619796816016610.1038/s41586‑023‑06123‑3 37258666
     [Google Scholar]
  51. FabriceA. Powering precision medicine through an international consortium.Cancer Discov.20177881883110.1158/2159‑8290.CD‑17‑0151 28572459
     [Google Scholar]
  52. JacobsF. CaniM. MalapelleU. NovelloS. NapoliV.M. BironzoP. Targeting Kras in NSCLC: Old failures and new options for “Non-G12c” patients.Cancers20211324633210.3390/cancers13246332 34944952
     [Google Scholar]
  53. AddeoA. BannaG.L. FriedlaenderA. KRAS G12C mutations in NSCLC: From target to resistance.Cancers20211311254110.3390/cancers13112541 34064232
     [Google Scholar]
  54. PlanchardD. PopatS. KerrK. NovelloS. SmitE.F. Faivre-FinnC. MokT.S. ReckM. Van SchilP.E. HellmannM.D. PetersS. Correction to: “Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”.Ann. Oncol.201930586387010.1093/annonc/mdy474 31987360
     [Google Scholar]
  55. HallinJ. EngstromL.D. HargisL. CalinisanA. ArandaR. BriereD.M. SudhakarN. BowcutV. BaerB.R. BallardJ.A. BurkardM.R. FellJ.B. FischerJ.P. VigersG.P. XueY. GattoS. Fernandez-BanetJ. PavlicekA. VelastaguiK. ChaoR.C. BartonJ. PierobonM. BaldelliE. PatricoinE.F.III CassidyD.P. MarxM.A. RybkinI.I. JohnsonM.L. OuS.H.I. LitoP. PapadopoulosK.P. JänneP.A. OlsonP. ChristensenJ.G. The KRASG12C inhibitor MRTX849 provides insight toward therapeutic susceptibility of Kras-mutant cancers in mouse models and patients.Cancer Discov.2020101547110.1158/2159‑8290.CD‑19‑1167 31658955
     [Google Scholar]
  56. PriorI.A. HoodF.E. HartleyJ.L. The frequency of Ras mutations in cancer.Cancer Res.202080142969297410.1158/0008‑5472.CAN‑19‑3682 32209560
     [Google Scholar]
  57. BaileyP. ChangD.K. NonesK. JohnsA.L. PatchA.M. GingrasM.C. MillerD.K. ChristA.N. BruxnerT.J.C. QuinnM.C. NourseC. MurtaughL.C. HarliwongI. IdrisogluS. ManningS. NourbakhshE. WaniS. FinkL. HolmesO. ChinV. AndersonM.J. KazakoffS. LeonardC. NewellF. WaddellN. WoodS. XuQ. WilsonP.J. CloonanN. KassahnK.S. TaylorD. QuekK. RobertsonA. PantanoL. MincarelliL. SanchezL.N. EversL. WuJ. PineseM. CowleyM.J. JonesM.D. ColvinE.K. NagrialA.M. HumphreyE.S. ChantrillL.A. MawsonA. HumphrisJ. ChouA. PajicM. ScarlettC.J. PinhoA.V. Giry-LaterriereM. RoomanI. SamraJ.S. KenchJ.G. LovellJ.A. MerrettN.D. ToonC.W. EpariK. NguyenN.Q. BarbourA. ZepsN. Moran-JonesK. JamiesonN.B. GrahamJ.S. DuthieF. OienK. HairJ. GrützmannR. MaitraA. Iacobuzio-DonahueC.A. WolfgangC.L. MorganR.A. LawlorR.T. CorboV. BassiC. RusevB. CapelliP. SalviaR. TortoraG. MukhopadhyayD. PetersenG.M. MunzyD.M. FisherW.E. KarimS.A. EshlemanJ.R. HrubanR.H. PilarskyC. MortonJ.P. SansomO.J. ScarpaA. MusgroveE.A. BaileyU.M.H. HofmannO. SutherlandR.L. WheelerD.A. GillA.J. GibbsR.A. PearsonJ.V. WaddellN. BiankinA.V. GrimmondS.M. Genomic analyses identify molecular subtypes of pancreatic cancer.Nature20165317592475210.1038/nature16965 26909576
     [Google Scholar]
  58. SiderisM. EminE.I. AbdullahZ. HanrahanJ. StefatouK.M. SevasV. EminE. HollingworthT. OdejinmiF. PapagrigoriadisS. VimplisS. WillmottF. The role of KRAS in endometrial cancer: A mini-review.Anticancer Res.201939253353910.21873/anticanres.13145 30711927
     [Google Scholar]
  59. RostyC. YoungJ.P. WalshM.D. ClendenningM. WaltersR.J. PearsonS. PavlukE. NaglerB. PakenasD. JassJ.R. JenkinsM.A. WinA.K. SoutheyM.C. ParryS. HopperJ.L. GilesG.G. WilliamsonE. EnglishD.R. BuchananD.D. Colorectal carcinomas with KRAS mutation are associated with distinctive morphological and molecular features.Mod. Pathol.201326682583410.1038/modpathol.2012.240 23348904
     [Google Scholar]
  60. HongD.S. FakihM.G. StricklerJ.H. DesaiJ. DurmG.A. ShapiroG.I. FalchookG.S. PriceT.J. SacherA. DenlingerC.S. BangY.J. DyG.K. KraussJ.C. KubokiY. KuoJ.C. CovelerA.L. ParkK. KimT.W. BarlesiF. MunsterP.N. RamalingamS.S. BurnsT.F. Meric-BernstamF. HenaryH. NgangJ. NgarmchamnanrithG. KimJ. HoukB.E. CanonJ. LipfordJ.R. FribergG. LitoP. GovindanR. LiB.T. KRAS G12C inhibition with sotorasib in advanced solid tumors.N. Engl. J. Med.2020383131207121710.1056/NEJMoa1917239 32955176
     [Google Scholar]
  61. RosenJ.C. SacherA. TsaoM.S. Direct GDP-KRAS G12C inhibitors and mechanisms of resistance: The tip of the iceberg.Ther. Adv. Med. Oncol.2023151758835923116014110.1177/17588359231160141 36950276
     [Google Scholar]
  62. SinghalA. StyersH.C. RubJ. LiZ. TorborgS.R. KimJ.Y. Grbovic-HuezoO. FengH. TarcanZ.C. Sahin OzkanH. HallinJ. BasturkO. YaegerR. ChristensenJ.G. BetelD. YanY. ChioI.I.C. de StanchinaE. TammelaT. A classical epithelial state drives acute resistance to Kras inhibition in pancreatic cancer.Cancer Discov.202414112122213410.1158/2159‑8290.CD‑24‑0740 38975873
     [Google Scholar]
  63. BannouraS.F. UddinM.H. NagasakaM. FaziliF. Al-HallakM.N. PhilipP.A. El-RayesB. AzmiA.S. Targeting KRAS in pancreatic cancer: New drugs on the horizon.Cancer Metastasis Rev.202140381983510.1007/s10555‑021‑09990‑2 34499267
     [Google Scholar]
  64. IsermannT. SersC. DerC.J. PapkeB. KRAS inhibitors: resistance drivers and combinatorial strategies.Trends Cancer20241129111610.1016/j.trecan.2024.11.009 39732595
     [Google Scholar]
  65. LokhandwalaJ. SmalleyT.B. TranT.H. Structural perspectives on recent breakthrough efforts toward direct drugging of RAS and acquired resistance.Front. Oncol.202414139470210.3389/fonc.2024.1394702 38841166
     [Google Scholar]
  66. WangX. IvetacA. KulykS. LawsonJ.D. MarxM.A. SmithC.R. Tetrahydropyridopyrimidine PAN-KRAS inhibitors.Patent WO2022133038A12022
  67. WangX. LawsonJ.D. MarxM.A. SmithC.R. KulykS. Azaquinazoline PAN-KRAS inhibitors.Patent WO2022132200A12022
  68. KulykS. WangX. PAN-KRAS inhibitors.Patent WO2023244599A12023
  69. WangX. IvetacA. KulykS. LawsonJ.D. MarxM.A. SmithC.R. Quinazoline PAN-KRAS inhibitors.Patent WO2023150284A22023
  70. WangX. KulykS. LawsonJ.D. MarxM.A. SmithC.R. Azaquinazoline PAN-KRAS inhibitors.Patent WO2023244615A12023
  71. WangX. IvetacA. KulykS. LawsonJ.D. MarxM.A. SmithC.R. Tetrahydropyridopyrimidine PAN-KRAS Inhibitors.Patent WO2023244604A12023
  72. WeiG. LinY. DingC. GongZ. PAN-KRAS inhibitor and preparation and application thereof.Patent CN114874201A2022
  73. JonesC.D. BhamraI. RyanJ. Quinazoline derivatives useful as Ras inhibitiors.Patent WO2022258974A12022
  74. JonesC.D. BhamraI. Pyrido[4,3-D]Pyrimidine compounds capable of inhibiting KRAS mutant proteins.Patent WO2022248885A22022
  75. BhamraI. JonesC.D. RyanJ. AylottH.E. Compounds.Patent WO2024115890A12024
  76. BroekerJ. AbbottJ. CuiJ. FesikS.W. GollnerA. HodgesT. LittleA. MantoulidisA. PhanJ. SarkarD. SunQ. WatersonA. SmethurstC.A.P. Annulated 2-Amino-3-cyano thiophenes and derivatives for the treatment of cancer.Patent WO2023099592A12023
  77. BroekerJ. AbbottJ. CuiJ. FesikS.W. FuchsJ. GollnerA. HerdeisL. HodgesT. LittleA. MantoulidisA. PhanJ. SarkarD. SunQ. WatersonA. SmethurstC.A.P. Annulated 2-Amino-3-Cyano thiophenes and derivatives for the treatment of cancer.Patent US20210380574A12021
  78. YiC. Pan-Kras inhibitors and uses thereof.Patent WO2023137223A12023
  79. WeiG. LinY. DiY. FangG. XuZ. ShiF. ZhaoT. ZhouJ. DingC. GongZ. Five-membered heterocyclic pyrimidine derivative and use thereof as inhibitor of Pan-Kras mutation.Patent WO2023138589A12023
  80. CuiJ.J. Kras inhibitors for treating disease.Patent WO2023/1730172023
  81. LiuX. WangY. WuM. FengX. ZengL. ZouP. WangY. YuX. PAN-KRAS inhibitors.Patent CN116969977A2023
  82. Heterocyclic substituted pyrimidopyran compound and use thereof.Patent WO WO2023246914A12023
  83. LiX. ShenF. CaiG. HeF. Fused piperidine compounds, preparation method thereof and application thereof in medicine.Patent CN117486901A2024
  84. ZhangZ. WangB. WallaceE. XuR. WehnP. YangY. LightstoneF. PeiJ. MaciagA.E. TurnerD.M. SimanshuD.K. ChanA.H.W. BrassardC.J. LiaoT. Compositions and methods for inhibition of Kras.Patent WO2024030633A12024
  85. YuC. ChenJ. BianY. LiX. SunH. LiuH. WangC. WangZ. Heterocyclic compounds, compositions thereof, and methods of treatment therewith.Patent WO2024032702A12024
  86. LajinessJ.P. GianatassioR.L. MarroneT.J. McclymontK.S. ValiereA. Pyridopyrimidine Kras inhibitors.Patent WO2024040131A12024
  87. FischerC. HendersonT. KawamuraS. MaX. MitcheltreeM.J. SlomanD.L. ChessariG. KobayakawaY. UnoT. OshimaT. SumiyamaK. SakamotoT. AkemotoK. MiuraR. Small molecule inhibitors of Kras proteins.Patent WO2024044667A22024
  88. WuH. XuR. YangX. LuY. HeJ. ShiZ. ZhaoZ. WangZ. LinY. ZhanB. LiB. LiS. DuY. WangD. KaiG.Q. FangL. ZhangH. LiT. ZhouQ. Pan-KRAS inhibitors and their use in medicine.Patent CN117736226A2024
  89. YinL. LiuX. Kras mutant protein inhibitor, preparation method therefor, and use thereof.Patent WO2024061333A12024
  90. RavetzB.D. TerrettJ.A. WeiB. ZengM. ShaoC. SunY. Oxazepine compounds comprising a 6-Aza moiety and uses thereof.Patent WO 2024083168A12024
  91. XiaoY. GuX. LaiK. Heterocyclic compound, pharmaceutical composition and application thereof. Patent CN117946135A2024
     [Google Scholar]
  92. XiaoY. GuX. LaiK. KRAS inhibitor compounds having macrocyclic structure.Patent CN117924327A2024
  93. LiX. ShenF. CaiG. WangW. HeF. Fused tricyclic compound, preparation method therefor, and pharmaceutical use thereof.Patent WO2024104453A12024
  94. HeistR.S. PatilT. RielyG.J. JacobsonJ.O. YangX. PerskyN.S. RootD.E. LiM. EngstromL.D. WatersL. LawsonJ.D. OlsonP. LitoP. OuS.I. Acquired resistance to KRASG12C inhibition in cancer.N. Engl. J. Med.2021384252382239310.1056/NEJMoa2105281
     [Google Scholar]
  95. AldeaM. AndreF. MarabelleA. DoganS. BarlesiF. SoriaJ.C. Overcoming resistance to tumor-targeted and immune-targeted therapies.Cancer Discov.202111487489910.1158/2159‑8290.CD‑20‑1638 33811122
     [Google Scholar]
  96. ZhaoY. Murciano-GoroffY.R. XueJ.Y. AngA. LucasJ. MaiT.T. Da Cruz PaulaA.F. SaikiA.Y. MohnD. AchantaP. SiskA.E. AroraK.S. RoyR.S. KimD. LiC. LimL.P. LiM. BahrA. LoomisB.R. de StanchinaE. Reis-FilhoJ.S. WeigeltB. BergerM. RielyG. ArbourK.C. LipfordJ.R. LiB.T. LitoP. Diverse alterations associated with resistance to KRAS(G12C) inhibition.Nature2021599788667968310.1038/s41586‑021‑04065‑2 34759319
     [Google Scholar]
  97. Di FedericoA. RicciottiI. FavoritoV. MichelinaS.V. ScaparoneP. MetroG. De GiglioA. PecciF. LambertiG. AmbrogioC. RicciutiB. Di FedericoA. Resistance to KRAS G12C inhibition in non-small cell lung cancer.Curr. Oncol. Rep.20232591017102910.1007/s11912‑023‑01436‑y 37378881
     [Google Scholar]
  98. CanonJ. RexK. SaikiA.Y. MohrC. CookeK. BagalD. GaidaK. HoltT. KnutsonC.G. KoppadaN. LanmanB.A. WernerJ. RapaportA.S. MiguelT.S. OrtizR. OsgoodT. SunJ. ZhuX. MccarterJ.D. VolakL.P. DesaiJ. KuoJ. GovindanR. HongD.S. OuyangW. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity.Nature201957521722310.1038/s41586‑019‑1694‑1
     [Google Scholar]
  99. SuzukiS. YonesakaK. TeramuraT. TakeharaT. KatoR. SakaiH. HarataniK. TanizakiJ. KawakamiH. HayashiH. SakaiK. NishioK. NakagawaK. KRAS inhibitor resistance in MET-amplified KRASG12C non-small cell lung cancer induced by RAS- and non-RAS-mediated cell signaling mechanisms.Clin. Cancer Res.202127205697570710.1158/1078‑0432.CCR‑21‑0856 34365406
     [Google Scholar]
  100. BriereD.M. LiS. CalinisanA. SudhakarN. ArandaR. HargisL. PengD.H. DengJ. EngstromL.D. HallinJ. GattoS. Fernandez-banetJ. PavlicekA. WongK. ChristensenJ.G. OlsonP. The KRASG12C inhibitor MRTX849 reconditions the tumor immune microenvironment and sensitizes tumors to checkpoint inhibitor therapy.Mol. Cancer Ther.202120697598510.1158/1535‑7163.MCT‑20‑0462 33722854
     [Google Scholar]
  101. JinZ. Potential therapeutic application of local anesthetics in cancer treatment.Recent Pat. Anticancer Drug Discov.202217432634210.2174/1574892817666220119121204 35043766
     [Google Scholar]
  102. LiuH. DilgerJ.P. LinJ. Effects of local anesthetics on cancer cells.Pharmacol. Ther.202021210755810.1016/j.pharmthera.2020.107558 32343985
     [Google Scholar]
  103. KerekE.M. Identification of drug resistance genes using a pooled lentiviral CRISPR/Cas9 screening approach.Methods Mol. Biol.2021238122724210.1007/978‑1‑0716‑1740‑3_13 34590280
     [Google Scholar]
  104. LiuH. WangP. CRISPR screening and cell line IC50 data reveal novel key genes for trametinib resistance.Clin. Exp. Med.2025242610.1007/s10238‑024‑01538‑2 39708249
     [Google Scholar]
  105. HofmannM.H. GerlachD. MisaleS. PetronczkiM. KrautN. Expanding the reach of precision oncology by drugging all KRAS mutants.Cancer Discov.202212492493710.1158/2159‑8290.CD‑21‑1331 35046095
     [Google Scholar]
  106. DrostenM. DhawahirA. SumE.Y.M. UrosevicJ. LechugaC.G. EstebanL.M. CastellanoE. GuerraC. SantosE. BarbacidM. Genetic analysis of Ras signalling pathways in cell proliferation, migration and survival.EMBO J.20102961091110410.1038/emboj.2010.7 20150892
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673372217250515031136
Loading
Analysis of Pan-Specific Inhibitors of Oncogenic Mutant Forms of KRAS GTPase
Curr. Med. Chem. 32, 9111 (2025); https://doi.org/10.2174/0109298673372217250515031136
/content/journals/cmc/10.2174/0109298673372217250515031136
/content/journals/cmc/10.2174/0109298673372217250515031136
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): BI-2865; Cancer; drug development; KRAS; KRAS-G12X/G13D/Q61H; mutations; pan-KRAS inhibitors; patents; RAS; SAR analysis

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