5F2E

Crystal Structure of small molecule ARS-853 covalently bound to K-Ras G12C

Summary for 5F2E

• Entry DOI: 10.2210/pdb5f2e/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, GLYCEROL, ... (7 entities in total)
• Functional Keywords: small gtpase domain, covalent inhibitor bound, switch ii pocket, gdp bound, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 1
• Total formula weight: 20512.49

Authors

Patricelli, M.P.,Janes, M.R.,Li, L.-S.,Hansen, R.,Peters, U.,Kessler, L.V.,Chen, Y.,Kucharski, J.M.,Feng, J.,Ely, T.,Chen, J.H.,Firdaus, S.J.,Babbar, A.,Ren, P.,Liu, Y. (deposition date: 2015-12-01, release date: 2016-01-13, Last modification date: 2024-11-20)

Primary citation

Patricelli, M.P.,Janes, M.R.,Li, L.S.,Hansen, R.,Peters, U.,Kessler, L.V.,Chen, Y.,Kucharski, J.M.,Feng, J.,Ely, T.,Chen, J.H.,Firdaus, S.J.,Babbar, A.,Ren, P.,Liu, Y.
Selective Inhibition of Oncogenic KRAS Output with Small Molecules Targeting the Inactive State.
Cancer Discov, 6:316-329, 2016

PubMed Abstract: KRAS gain-of-function mutations occur in approximately 30% of all human cancers. Despite more than 30 years of KRAS-focused research and development efforts, no targeted therapy has been discovered for cancers with KRAS mutations. Here, we describe ARS-853, a selective, covalent inhibitor of KRAS(G12C) that inhibits mutant KRAS-driven signaling by binding to the GDP-bound oncoprotein and preventing activation. Based on the rates of engagement and inhibition observed for ARS-853, along with a mutant-specific mass spectrometry-based assay for assessing KRAS activation status, we show that the nucleotide state of KRAS(G12C) is in a state of dynamic flux that can be modulated by upstream signaling factors. These studies provide convincing evidence that the KRAS(G12C) mutation generates a "hyperexcitable" rather than a "statically active" state and that targeting the inactive, GDP-bound form is a promising approach for generating novel anti-RAS therapeutics.

PubMed: 26739882
DOI: 10.1158/2159-8290.CD-15-1105

Experimental method

X-RAY DIFFRACTION (1.4 Å)