Abstract PL04-03: Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions.

Somatic mutations in the small GTPase K-Ras are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies^1-3. Efforts to directly target this oncogene have faced difficulties due to its picomolar affinity for GTP/GDP⁴ and the absence of known allosteric regulatory sites.Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis^5,6. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent upon relative nucleotide affinity and concentration. This gives GTP an advantage over GDP⁷ and increases the proportion of active GTP-bound Ras. Here, we report the development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras G12C.These compounds rely on the mutant cysteine for binding and therefore do not affect the wild type protein (WT). Crystallographic studies reveal the formation of a new pocket that is not apparent in previous structures of Ras, beneath the effector binding switch-II region. Binding of these inhibitors to K-Ras G12C disrupts both switch-I and switch-II, subverting the native nucleotide preference to favor GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a novel allosteric regulatory site on Ras that is targetable in a mutant specific manner.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):PL04-03.

Citation Format: Jonathan M. Ostrem, Ulf Peters, Martin L. Sos, James A. Wells, Kevan M. Shokat. Selective inhibition of K-Ras G12C through allosteric control of GTP affinity and effector interactions. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr PL04-03.