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 therapies1,2,3. Efforts to target this oncogene directly have faced difficulties owing 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 hydrolysis5,6. With diminished regulation by GTPase activity, the nucleotide state of Ras becomes more dependent on 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. 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 favour GDP over GTP and impairing binding to Raf. Our data provide structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner.
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Protein Data Bank
Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank (PDB), and accession numbers can be found in Extended Data Table 2.
We are grateful to M. Burlingame and J. Sadowsky for assistance with the tethering screen; P. Ren and Y. Liu for assistance in chemical design and discussions; N. Younger for preparing several compounds; J. Kuriyan for sharing SOS and H-Ras constructs; F. McCormick and T. Yuan for discussion and sharing K-Ras reagents; R. Goody, K. Shannon and F. Wittinghofer for discussion. U.P. was supported by a postdoctoral fellowship of the Tobacco-related Disease Research Program (19FT-0069). The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the US Department of Energy under Contract No. DE-AC02-05CH11231. M.L.S. is a fellow of the International Association for the Study of Lung Cancer (IASLC) and receives a Young Investigator Award of the Prostate Cancer Foundation (PCF).
Extended data figures
Extended data tables
This file contains Supplementary Text and Data, additional references and Supplementary Table 1.
About this article
Chinese Journal of Chemistry (2019)