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143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models

Acta Pharmacologica Sinica volume 44, pages 1475–1486 (2023)Cite this article

Abstract

The KRASG12C mutant has emerged as an important therapeutic target in recent years. Covalent inhibitors have shown promising antitumor activity against KRASG12C-mutant cancers in the clinic. In this study, a structure-based and focused chemical library analysis was performed, which led to the identification of 143D as a novel, highly potent and selective KRASG12C inhibitor. The antitumor efficacy of 143D in vitro and in vivo was comparable with that of AMG510 and of MRTX849, two well-characterized KRASG12C inhibitors. At low nanomolar concentrations, 143D showed biochemical and cellular potency for inhibiting the effects of the KRASG12C mutation. 143D selectively inhibited cell proliferation and induced G1-phase cell cycle arrest and apoptosis by downregulating KRASG12C-dependent signal transduction. Compared with MRTX849, 143D exhibited a longer half-life and higher maximum concentration (Cmax) and area under the curve (AUC) values in mouse models, as determined by tissue distribution assays. Additionally, 143D crossed the blood‒brain barrier. Treatment with 143D led to the sustained inhibition of KRAS signaling and tumor regression in KRASG12C-mutant tumors. Moreover, 143D combined with EGFR/MEK/ERK signaling inhibitors showed enhanced antitumor activity both in vitro and in vivo. Taken together, our findings indicate that 143D may be a promising drug candidate with favorable pharmaceutical properties for the treatment of cancers harboring the KRASG12C mutation.

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Fig. 1: 143D shows selective binding to KRASG12C.
Fig. 2: 143D displays selective cytotoxicity in KRASG12C-mutant cells.
Fig. 3: 143D selectively inhibits the constitutive activation of KRASG12C signaling pathways.
Fig. 4: 143D inhibits KRASG12C-mutant tumor growth by targeting the KRAS pathway.
Fig. 5: Combined 143D with inhibitors of EGFR/MEK/ERK signaling results in enhanced antitumor effects.

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References

  1. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13:828–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Pylayeva-Gupta Y, Grabocka E, Bar-Sagi D. RAS oncogenes: weaving a tumorigenic web. Nat Rev Cancer. 2011;11:761–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Stephen AG, Esposito D, Bagni RK, McCormick F. Dragging ras back in the ring. Cancer Cell. 2014;25:272–81.

    Article  CAS  PubMed  Google Scholar 

  4. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.

    Article  CAS  PubMed  Google Scholar 

  5. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170:17–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hobbs GA, Der CJ, Rossman KL. RAS isoforms and mutations in cancer at a glance. J Cell Sci. 2016;129:1287–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Lu S, Jang H, Gu S, Zhang J, Nussinov R. Drugging Ras GTPase: a comprehensive mechanistic and signaling structural view. Chem Soc Rev. 2016;45:4929–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hofmann MH, Gmachl M, Ramharter J, Savarese F, Gerlach D, Marszalek JR, et al. BI-3406, a potent and selective SOS1-KRAS interaction inhibitor, is effective in KRAS-driven cancers through combined MEK inhibition. Cancer Discov. 2021;11:142–57.

    Article  CAS  PubMed  Google Scholar 

  9. Moore AR, Rosenberg SC, McCormick F, Malek S. RAS-targeted therapies: is the undruggable drugged? Nat Rev Drug Discov. 2020;19:533–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Canon J, Rex K, Saiki AY, Mohr C, Cooke K, Bagal D, et al. The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity. Nature. 2019;575:217–23.

    Article  CAS  PubMed  Google Scholar 

  11. Ostrem JM, Peters U, Sos ML, Wells JA, Shokat KM. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature. 2013;503:548–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Nagasaka M, Li Y, Sukari A, Ou SI, Al-Hallak MN, Azmi AS. KRAS G12C Game of Thrones, which direct KRAS inhibitor will claim the iron throne? Cancer Treat Rev. 2020;84:101974.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hallin J, Engstrom LD, Hargis L, Calinisan A, Aranda R, Briere DM, et al. The KRAS(G12C) inhibitor MRTX849 provides insight toward therapeutic susceptibility of KRAS-mutant cancers in mouse models and patients. Cancer Discov. 2020;10:54–71.

    Article  CAS  PubMed  Google Scholar 

  14. Gentile DR, Rathinaswamy MK, Jenkins ML, Moss SM, Siempelkamp BD, Renslo AR, et al. Ras binder induces a modified Switch-II pocket in GTP and GDP states. Cell Chem Biol. 2017;24:1455–66.e14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Qin Y, Dai W, Wang Y, Gong XG, Lu M. Fe-SOD cooperates with Nutlin3 to selectively inhibit cancer cells in vitro and in vivo. Biochem Biophys Res Commun. 2013;431:169–75.

    Article  CAS  PubMed  Google Scholar 

  16. McCormick F. KRAS as a therapeutic target. Clin Cancer Res. 2015;21:1797–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ryan MB, Fece de la Cruz F, Phat S, Myers DT, Wong E, Shahzade HA, et al. Vertical pathway inhibition overcomes adaptive feedback resistance to KRAS(G12C) inhibition. Clin Cancer Res. 2020;26:1633–43.

    Article  CAS  PubMed  Google Scholar 

  18. Misale S, Fatherree JP, Cortez E, Li C, Bilton S, Timonina D, et al. KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition. Clin Cancer Res. 2019;25:796–807.

    Article  CAS  PubMed  Google Scholar 

  19. Fell JB, Fischer JP, Baer BR, Blake JF, Bouhana K, Briere DM, et al. Identification of the clinical development candidate MRTX849, a covalent KRAS(G12C) inhibitor for the treatment of cancer. J Med Chem. 2020;63:6679–93.

    Article  CAS  PubMed  Google Scholar 

  20. Akhave NS, Biter AB, Hong DS. Mechanisms of resistance to KRAS(G12C)-targeted therapy. Cancer Discov. 2021;11:1345–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu S, Jang H, Muratcioglu S, Gursoy A, Keskin O, Nussinov R, et al. Ras conformational ensembles, allostery, and signaling. Chem Rev. 2016;116:6607–65.

    Article  CAS  PubMed  Google Scholar 

  22. De Luca A, Maiello MR, D’Alessio A, Pergameno M, Normanno N. The RAS/RAF/MEK/ERK and the PI3K/AKT signalling pathways: role in cancer pathogenesis and implications for therapeutic approaches. Expert Opin Ther Targets. 2012;16:S17–27.

    Article  PubMed  Google Scholar 

  23. Downward J. Targeting RAS and PI3K in lung cancer. Nat Med. 2008;14:1315–6.

    Article  CAS  PubMed  Google Scholar 

  24. Sabari JK, Velcheti V, Shimizu K, Strickland MR, Heist RS, Singh M, et al. Activity of Adagrasib (MRTX849) in brain metastases: preclinical models and clinical data from patients with KRASG12C-mutant non-small cell lung cancer. Clin Cancer Res. 2022;28:3318–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lorthiois E, Barys L, Beyer KS, Bomio-Confaglia C, Burks H, Chen X, et al. Discovery, preclinical characterization, and early clinical activity of JDQ443, a structurally novel, potent, and selective covalent oral inhibitor of KRASG12C. Cancer Discov. 2022;12:1500–17.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chakraborty A. KRASG12C inhibitor: combing for combination. Biochem Soc Trans. 2020;48:2691–701.

    Article  CAS  PubMed  Google Scholar 

  27. Prior IA, Hood FE, Hartley JL. The frequency of ras mutations in cancer. Cancer Res. 2020;80:2969–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;32:1101–10.

    Article  CAS  PubMed  Google Scholar 

  29. Koga T, Suda K, Fujino T, Ohara S, Hamada A, Nishino M, et al. KRAS secondary mutations that confer acquired resistance to KRAS G12C inhibitors, sotorasib and adagrasib, and overcoming strategies: insights from in vitro experiments. J Thorac Oncol. 2021;16:1321–32.

    Article  CAS  PubMed  Google Scholar 

  30. Molina-Arcas M, Moore C, Rana S, Van Maldegem F, Mugarza E, Romero-Clavijo P, et al. Development of combination therapies to maximize the impact of KRAS-G12C inhibitors in lung cancer. Sci Transl Med. 2019;11:eaaw7999.

  31. Warmuth M, Kim S, Gu XJ, Xia G, Adrian F. Ba/F3 cells and their use in kinase drug discovery. Curr Opin Oncol. 2007;19:55–60.

    Article  CAS  PubMed  Google Scholar 

  32. Janes MR, Zhang J, Li LS, Hansen R, Peters U, Guo X, et al. Targeting KRAS mutant cancers with a covalent G12C-specific inhibitor. Cell. 2018;172:578–89.e17.

    Article  CAS  PubMed  Google Scholar 

  33. Retmana IA, Loos NHC, Schinkel AH, Beijnen JH, Sparidans RW. Quantification of KRAS inhibitor sotorasib in mouse plasma and tissue homogenates using liquid chromatography-tandem mass spectrometry. J Chromatogr B Anal Technol Biomed Life Sci. 2021;1174:122718.

    Article  CAS  Google Scholar 

  34. Ryan MB, Coker O, Sorokin A, Fella K, Barnes H, Wong E, et al. KRAS(G12C)-independent feedback activation of wild-type RAS constrains KRAS(G12C) inhibitor efficacy. Cell Rep. 2022;39:110993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Corcoran RB, Ebi H, Turke AB, Coffee EM, Nishino M, Cogdill AP, et al. EGFR-mediated re-activation of MAPK signaling contributes to insensitivity of BRAF mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discov. 2012;2:227–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Mirzoeva OK, Das D, Heiser LM, Bhattacharya S, Siwak D, Gendelman R, et al. Basal subtype and MAPK/ERK kinase (MEK)-phosphoinositide 3-kinase feedback signaling determine susceptibility of breast cancer cells to MEK inhibition. Cancer Res. 2009;69:565–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tang D, Kroemer G, Kang R. Oncogenic KRAS blockade therapy: renewed enthusiasm and persistent challenges. Mol Cancer. 2021;20:128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Brown WS, McDonald PC, Nemirovsky O, Awrey S, Chafe SC, Schaeffer DF, et al. Overcoming adaptive resistance to KRAS and MEK inhibitors by co-targeting mTORC1/2 complexes in pancreatic cancer. Cell Rep Med. 2020;1:100131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013;73:1245–54.

    Article  PubMed  Google Scholar 

  40. Kamioka Y, Yasuda S, Fujita Y, Aoki K, Matsuda M. Multiple decisive phosphorylation sites for the negative feedback regulation of SOS1 via ERK. J Biol Chem. 2010;285:33540–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Tanaka N, Lin JJ, Li C, Ryan MB, Zhang J, Kiedrowski LA, et al. Clinical acquired resistance to KRAS(G12C) inhibition through a novel KRAS Switch-II pocket mutation and polyclonal alterations converging on RAS-MAPK reactivation. Cancer Discov. 2021;11:1913–22.

    Article  CAS  Google Scholar 

  42. Jiao D, Yang S. Overcoming resistance to drugs targeting KRAS(G12C) mutation. Innovation (Camb). 2020;1:100035.

    CAS  PubMed  Google Scholar 

  43. Ying H, Kimmelman AC, Lyssiotis CA, Hua S, Chu GC, Fletcher-Sananikone E, et al. Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism. Cell. 2012;149:656–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Piffoux M, Eriau E, Cassier PA. Autophagy as a therapeutic target in pancreatic cancer. Br J Cancer. 2021;124:333–44.

    Article  PubMed  Google Scholar 

  45. Seegobin K, Majeed U, Wiest N, Manochakian R, Lou Y, Zhao Y. Immunotherapy in non-small cell lung cancer with actionable mutations other than EGFR. Front Oncol. 2021;11:750657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by grants from the Natural Science Foundation of Shanghai (19ZR1467700), the Lingang Laboratory (LG202101-01-06) and the Major Research Plan of the National Natural Science Foundation of China (91953000). We also express our sincere gratitude to our mentor Academician Hua-liang Jiang for his enlightening mentoring and strong support throughout this study, and our deep sorrow for the loss of him, who passed away on December 23rd, 2022.

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Authors and Affiliations

  1. The First Affiliated Hospital of USTC (Anhui Provincial Hospital), Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, China

    Lan-song Xu & Hua-liang Jiang

  2. Drug Discovery and Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China

    Lan-song Xu, Xiang-tai Kong, Ming-yue Zheng, Hua-liang Jiang & Cheng-ying Xie

  3. Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China

    Lan-song Xu, Ke-xin Yang, Ya-fang Wang, Ming-yue Zheng, Hua-liang Jiang & Cheng-ying Xie

  4. School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China

    Lan-song Xu, Ke-xin Yang, Ya-fang Wang, Hua-liang Jiang & Cheng-ying Xie

  5. Suzhou AlphaMa Biotechnology Co., Ltd., Suzhou, 215123, China

    Su-xin Zheng

  6. Suzhou Institute of Drug Innovation, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Suzhou, 215123, China

    Liang-he Mei & Qiang Zhou

  7. Lingang Laboratory, Shanghai, 200031, China

    Hua-liang Jiang & Cheng-ying Xie

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Contributions

LSX performed the protein purification, mass spectrometry assays and molecular assays. LSX, KXY, and YFW performed the cell assays. CYX was responsible for the in vivo and in vivo antitumor assays. SXZ, LHM, and QZ performed the compound design and synthesis, PK and tissue distribution experiments. XTK was responsible for molecular docking experiments. HLJ, CYX and MYZ designed the project and analyzed the data. LSX and CYX were responsible for drafting the manuscript.

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Correspondence to Ming-yue Zheng or Cheng-ying Xie.

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Xu, Ls., Zheng, Sx., Mei, Lh. et al. 143D, a novel selective KRASG12C inhibitor exhibits potent antitumor activity in preclinical models. Acta Pharmacol Sin 44, 1475–1486 (2023). https://doi.org/10.1038/s41401-023-01053-2

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