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Direct RAS inhibitors turn 10

Nature Chemical Biology (2024)Cite this article

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RAS proteins, central drivers of cancer, appeared ‘undruggable’ for almost 30 years. Here we provide a personal perspective on the effort leading to our initial report of KRASG12C inhibitors in 2013, and the decade of discoveries that followed.

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Fig. 1: Evolution of KRas inhibitors from tethering fragments to approved drugs.

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Authors and Affiliations

  1. Department of Medicine, University of California, San Francisco, San Francisco, CA, USA

    Jonathan M. L. Ostrem

  2. Kumquat Biosciences, San Diego, CA, USA

    Ulf Peters

  3. Department of Cellular and Molecular Pharmacology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA, USA

    Kevan M. Shokat

  4. Department of Chemistry, University of California, Berkeley, Berkeley, CA, USA

    Kevan M. Shokat

Authors
  1. Jonathan M. L. Ostrem
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  2. Ulf Peters
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  3. Kevan M. Shokat
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Corresponding author

Correspondence to Jonathan M. L. Ostrem.

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Competing interests

K.M.S. has received stock and monetary compensation from KRASG12C patents licensed to Araxes Pharma, and currently receives stock and/or monetary compensation from: Apertor, BioTheryX, BridGene Biosciences, Denali Therapeutics, eFFECTOR Therapeutics, Erasca, G Protein Therapeutics, Genentech/Roche, Ikena, Initial Therapeutics, Lyterian, Kumquat Biosciences, Kura Oncology, Merck, Mitokinin, Montara, Nested, Nextech, Radd Pharma, Revolution Medicines, Rezo, Totus, Turning Point, Type6 Therapeutics, Wellspring Biosciences (Araxes Pharma), Vevo and Vicinitas. U.P. has received stock and monetary compensation from KRASG12C patents licensed to Araxes Pharma, and currently receives stock and/or monetary compensation from Araxes Pharma and Kumquat Biosciences. J.M.L.O. has received stock and monetary compensation from KRASG12C patents licensed to Araxes Pharma.

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Ostrem, J.M.L., Peters, U. & Shokat, K.M. Direct RAS inhibitors turn 10. Nat Chem Biol (2024). https://doi.org/10.1038/s41589-024-01691-5

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