Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS <sup>G12C</sup> Inhibitor
Joachim Bröker, Alex G. Waterson, Chris A. Smethurst, Dirk Kessler, Jark Böttcher, Moriz Mayer, Gerhard Gmaschitz, Jason Phan, Andrew J. Little, Jason R. Abbott, Qi Sun, Michael Gmachl, Dorothea Rudolph, Heribert Arnhof, Klaus Rumpel, Fabio Savarese, Thomas Gerstberger, Nikolai Mischerikow, Matthias Treu, Lorenz Herdeis, Tobias Wunberg, Andreas Gollner, Harald Weinstabl, Andreas Mantoulidis, Oliver Krämer, Darryl B. McConnell, Stephen W. Fesik
Abstract
inhibitors but also provides a starting point for the discovery of inhibitors against other oncogenic KRAS mutants.
Topics & Concepts
KRASChemistryIn vivoSmall moleculeCovalent bondCysteineBinding sitePoint mutationMutantBiochemistryMutationEnzymeGeneticsBiologyGeneOrganic chemistryProtein Kinase Regulation and GTPase SignalingMelanoma and MAPK PathwaysEnzyme Structure and Function