K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions

By J. Ostrem, U. Peters, M. Sos, J. Wells, Kevan M. Shokat. Nature, 2013

2,245 citations recorded by the source corpus.

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. Efforts to target this oncogene directly have faced difficulties owing to its picomolar affinity for GTP/GDP and the absence of known allosteric regulatory sites. Oncogenic mutations result in functional activation of Ras family proteins by impairing GTP hydrolysis. 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 GDP 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.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/7d6a21edd0843a482abc37efa80674fdc4bc111d

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In Molecular Biology

1. Michelle Arkin
2. K. Rossman
3. Yinyan Tang
4. C. Der
5. C. Zappa
6. Kevan M. Shokat
7. C. V. Dang
8. E. Reddy

Citations in the corpus

• Organoid profiling identifies common responders to chemotherapy in pancreatic cancer (2018, background): “To date, PDAC driver mutations have been hard to target in the clinical 109 setting, with the exception of microsatellite instability (8), BRCA2 mutations (9) and potentially targetable, 110 uncommon KRAS mutations (10).”
• Drugging the ‘undruggable’ cancer targets (2017, positive): “An important breakthrough in developing compounds that bind to RAS and inhibit its activity was achieved by Kevan Shokat’s group, who showed that the KRAS G12C mutation creates a pocket that could be exploited to synthesize a covalent inhibitor specific to this mutant protein 11 .”
• Biochemical and Structural Analysis of Common Cancer-Associated KRAS Mutations (2015, background): “KRASG12C, inparticular, has been the subject of efforts todirectly target that specific oncogenic KRAS subtype and numerous structures were solved as part of that effort (34, 46).”
• The design and development of covalent protein-protein interaction inhibitors for cancer treatment (2020, background): “Zeng M, Lu J, Li L, Feru F, Quan C, Gero TW, et al. Potent and selective covalent quinazoline inhibitors of KRAS G12C.”
• RAS isoforms and mutations in cancer at a glance (2016, background): “The development of G12Cselective inhibitors that target the thiol in order to inhibit GTP binding – locking RAS in an inactive state so it cannot interact with its effectors – have been recently described (Hunter et al., 2014; Ostrem et al., 2013).”