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

Acta Pharmacologica Sinica (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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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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  1. Lan-song Xu
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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.

Corresponding authors

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 (2023). https://doi.org/10.1038/s41401-023-01053-2

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  • DOI: https://doi.org/10.1038/s41401-023-01053-2

Keywords

  • KRASG12C
  • MAPK signaling pathway
  • small-molecule inhibitor
  • synergistic effect
  • 143D

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