K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions
TLDR
The development of small molecules that irreversibly bind to a common oncogenic mutant, K-Ras(G12C) and structure-based validation of a new allosteric regulatory site on Ras that is targetable in a mutant-specific manner are provided.Abstract:
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.read more
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References
More filters
Journal ArticleDOI
Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1
David A. Barbie,Pablo Tamayo,Jesse S. Boehm,So Young Kim,Susan Moody,Ian F. Dunn,Anna C. Schinzel,Peter Sandy,Etienne Meylan,Claudia Scholl,Stefan Fröhling,Edmond M. Chan,Martin L. Sos,Kathrin Michel,Craig H. Mermel,Serena J. Silver,Barbara A. Weir,Jan H. Reiling,Qing Sheng,Piyush Gupta,Raymond C. Wadlow,Raymond C. Wadlow,Hanh Le,Sebastian Hoersch,Ben S. Wittner,Ben S. Wittner,Sridhar Ramaswamy,Sridhar Ramaswamy,David M. Livingston,David M. Sabatini,Matthew Meyerson,Matthew Meyerson,Roman K. Thomas,Eric S. Lander,Jill P. Mesirov,David E. Root,D. Gary Gilliland,Tyler Jacks,William C. Hahn +38 more
TL;DR: Observations indicate that TBK1 and NF-κB signalling are essential in KRAS mutant tumours, and establish a general approach for the rational identification of co-dependent pathways in cancer.
Journal ArticleDOI
KRAS Mutation Status Is Predictive of Response to Cetuximab Therapy in Colorectal Cancer
Astrid Lièvre,Jean-Baptiste Bachet,Delphine Le Corre,Valérie Boige,Bruno Landi,Jean-François Emile,Jean-François Côté,Gorana Tomasic,Christophe Penna,Michel Ducreux,Philippe Rougier,Frédérique Penault-Llorca,Pierre Laurent-Puig +12 more
TL;DR: KRAS mutations are a predictor of resistance to cetuximab therapy and are associated with a worse prognosis, and the EGFR amplification, which is not as frequent as initially reported, is also associated with response to this treatment.
Journal ArticleDOI
KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib
William Pao,Theresa Y Wang,Gregory J. Riely,Vincent A. Miller,Qiulu Pan,Marc Ladanyi,Maureen F. Zakowski,Robert T. Heelan,Mark G. Kris,Harold E. Varmus +9 more
TL;DR: It is shown that mutations in KRAS are associated with a lack of sensitivity to either gefitinib or erlotinib, suggesting that treatment decisions regarding use of these kinase inhibitors might be improved by determining the mutational status of both EGFR and KRAS.
Journal ArticleDOI
A cytoplasmic protein stimulates normal N-ras p21 GTPase, but does not affect oncogenic mutants
Meg Trahey,Frank McCormick +1 more
TL;DR: In Xenopus oocytes, this protein maintains normal p21 in a biologically inactive, GDP-bound state through its effect on GTPase activity, and it appears that the major effect of position 12 mutations is to prevent this protein from stimulating p21 GTP enzyme activity, thereby allowing these mutants to remain in the active GTP- bound state.
Journal ArticleDOI
Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins
M. V. Milburn,Liang Tong,Abraham M. deVos,Axel T. Brunger,Ziro Yamaizumi,Susumu Nishimura,Sung-Hou Kim +6 more
TL;DR: A comparison of eight three-dimensional structures of ras proteins in four different crystal lattices reveals that the "on" and "off" states of the switch are distinguished by conformational differences that span a length of more than 40 A, and are induced by the gamma-phosphate.
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