2. Academic Validation
  3. Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor

Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor

  • J Med Chem. 2022 Nov 10;65(21):14614-14629. doi: 10.1021/acs.jmedchem.2c01120.
Joachim Bröker 1,  Alex G Waterson 2,  Chris Smethurst 1,  Dirk Kessler 1,  Jark Böttcher 1,  Moriz Mayer 1,  Gerhard Gmaschitz 1,  Jason Phan 2,  Andrew Little 2,  Jason R Abbott 2,  Qi Sun 2,  Michael Gmachl 1,  Dorothea Rudolph 1,  Heribert Arnhof 1,  Klaus Rumpel 1,  Fabio Savarese 1,  Thomas Gerstberger 1,  Nikolai Mischerikow 1,  Matthias Treu 1,  Lorenz Herdeis 1,  Tobias Wunberg 1,  Andreas Gollner 1,  Harald Weinstabl 1,  Andreas Mantoulidis 1,  Oliver Krämer 1,  Darryl B McConnell 1,  Stephen W Fesik 2
Affiliations

Affiliations

  • 1 Boehringer Ingelheim RCV GmbH & Co. KG, Dr. Boehringer Gasse 5-11, A-1121 Vienna, Austria.
  • 2 Department of Biochemistry, Vanderbilt University School of Medicine, 2215 Garland Avenue, 607 Light Hall, Nashville, Tennessee 37232-0146, United States.
PMID: 36300829 DOI: 10.1021/acs.jmedchem.2c01120
Abstract

Activating mutations in KRAS are the most frequent oncogenic alterations in Cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRASG12C inhibitors. To date, KRASG12C inhibitors have been discovered by first covalently binding to the cysteine at position 12 and then optimizing pocket binding. We report on the discovery of the in vivo active KRASG12C inhibitor BI-0474 using a different approach, in which small molecules that bind reversibly to the switch II pocket were identified and then optimized for non-covalent binding using structure-based design. Finally, the Michael acceptor containing warhead was attached. Our approach offers not only an alternative approach to discovering KRASG12C inhibitors but also provides a starting point for the discovery of inhibitors against Other oncogenic KRAS mutants.

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