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Discovery of N-(1-Acryloylazetidin-3-yl)-2-(1H-indol-1-yl)acetamides as Covalent Inhibitors of KRASG12C

  • Youngsook Shin
    Youngsook Shin
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Joon Won Jeong
    Joon Won Jeong
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
  • Ryan P. Wurz
    Ryan P. Wurz
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Ryan P. Wurz
  • Pragathi Achanta
    Pragathi Achanta
    Oncology Research, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Tara Arvedson
    Tara Arvedson
    Oncology Research, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Michael D. Bartberger
    Michael D. Bartberger
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Iain D. G. Campuzano
    Iain D. G. Campuzano
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Ray Fucini
    Ray Fucini
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
    More by Ray Fucini
  • Stig K. Hansen
    Stig K. Hansen
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
  • John Ingersoll
    John Ingersoll
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Jeffrey S. Iwig
    Jeffrey S. Iwig
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
  • J. Russell Lipford
    J. Russell Lipford
    Oncology Research, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Vu Ma
    Vu Ma
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Vu Ma
  • David J. Kopecky
    David J. Kopecky
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • John McCarter
    John McCarter
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Tisha San Miguel
    Tisha San Miguel
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Christopher Mohr
    Christopher Mohr
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Sudi Sabet
    Sudi Sabet
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
    More by Sudi Sabet
  • Anne Y. Saiki
    Anne Y. Saiki
    Oncology Research, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Andrew Sawayama
    Andrew Sawayama
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
  • Steven Sethofer
    Steven Sethofer
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
  • Christopher M. Tegley
    Christopher M. Tegley
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Laurie P. Volak
    Laurie P. Volak
    Pharmacokinetics and Drug Metabolism, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Kevin Yang
    Kevin Yang
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
    More by Kevin Yang
  • Brian A. Lanman
    Brian A. Lanman
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
  • Daniel A. Erlanson*
    Daniel A. Erlanson
    Carmot Therapeutics, Inc. 740 Heinz Avenue, Berkeley, California 94710, United States
    *Tel: 415-407-8080. E-mail: [email protected]
  • , and 
  • Victor J. Cee*
    Victor J. Cee
    Departments of Therapeutic Discovery, Amgen Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States
    *Tel: 805-313-5500. E-mail: [email protected]
Cite this: ACS Med. Chem. Lett. 2019, 10, 9, 1302–1308
Publication Date (Web):August 20, 2019
https://doi.org/10.1021/acsmedchemlett.9b00258
Copyright © 2019 American Chemical Society

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    Abstract

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    KRAS regulates many cellular processes including proliferation, survival, and differentiation. Point mutants of KRAS have long been known to be molecular drivers of cancer. KRAS p.G12C, which occurs in approximately 14% of lung adenocarcinomas, 3–5% of colorectal cancers, and low levels in other solid tumors, represents an attractive therapeutic target for covalent inhibitors. Herein, we disclose the discovery of a class of novel, potent, and selective covalent inhibitors of KRASG12C identified through a custom library synthesis and screening platform called Chemotype Evolution and structure-based design. Identification of a hidden surface groove bordered by H95/Y96/Q99 side chains was key to the optimization of this class of molecules. Best-in-series exemplars exhibit a rapid covalent reaction with cysteine 12 of GDP-KRASG12C with submicromolar inhibition of downstream signaling in a KRASG12C-specific manner.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsmedchemlett.9b00258.

    • Experimental details and synthetic scheme. Crystallography table of statistics. Mean, standard deviation, and n for biological replicates (PDF)

    Accession Codes

    The X-ray cocrystal structures have been deposited with the Protein Data Bank under Accession ID codes 6P8W, 6P8X, 6P8Y, and 6P8Z.

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    Electronic Supporting Information files are available without a subscription to ACS Web Editions. The American Chemical Society holds a copyright ownership interest in any copyrightable Supporting Information. Files available from the ACS website may be downloaded for personal use only. Users are not otherwise permitted to reproduce, republish, redistribute, or sell any Supporting Information from the ACS website, either in whole or in part, in either machine-readable form or any other form without permission from the American Chemical Society. For permission to reproduce, republish and redistribute this material, requesters must process their own requests via the RightsLink permission system. Information about how to use the RightsLink permission system can be found at http://pubs.acs.org/page/copyright/permissions.html.

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