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

doi:10.1021/acs.jmedchem.2c01120

Article

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

Journal of medicinal chemistry - 10 Nov 2022

Bröker Joachim, Waterson Alex G, Smethurst Chris, Kessler Dirk, Böttcher Jark, Mayer Moriz, Gmaschitz Gerhard, Phan Jason, Little Andrew, Abbott Jason R, Sun Qi, Gmachl Michael, Rudolph Dorothea, Arnhof Heribert, Rumpel Klaus, Savarese Fabio, Gerstberger Thomas, Mischerikow Nikolai, Treu Matthias, Herdeis Lorenz, Wunberg Tobias, Gollner Andreas, Weinstabl Harald, Mantoulidis Andreas, Krämer Oliver, McConnell Darryl B, W Fesik Stephen

Abstract excerpt

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...

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

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