6B0Y

Crystal Structure of small molecule ARS-917 covalently bound to K-Ras G12C

Summary for 6B0Y

• Entry DOI: 10.2210/pdb6b0y/pdb
• Related: 6B0V
• Descriptor: GTPase KRas, CALCIUM ION, 1-{4-[6-chloro-7-(2-fluorophenyl)quinazolin-4-yl]piperazin-1-yl}propan-1-one, ... (6 entities in total)
• Functional Keywords: small gtpase domain, covalent inhibitor bound, switch ii pocket, gdp bound, signaling protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 40826.29

Authors

Hansen, R.,Peters, U.,Babbar, A.,Chen, Y.,Feng, J.,Janes, M.R.,Li, L.-S.,Ren, P.,Liu, Y.,Zarrinkar, P.P. (deposition date: 2017-09-15, release date: 2018-05-16, Last modification date: 2024-10-30)

Primary citation

Hansen, R.,Peters, U.,Babbar, A.,Chen, Y.,Feng, J.,Janes, M.R.,Li, L.S.,Ren, P.,Liu, Y.,Zarrinkar, P.P.
The reactivity-driven biochemical mechanism of covalent KRASG12Cinhibitors.
Nat. Struct. Mol. Biol., 25:454-462, 2018

PubMed Abstract: Activating mutations in KRAS are among the most common tumor driver mutations. Until recently, KRAS had been considered undruggable with small molecules; the discovery of the covalent KRAS inhibitors ARS-853 and ARS-1620 has demonstrated that it is feasible to inhibit KRAS with high potency in cells and animals. Although the biological activity of these inhibitors has been described, the biochemical mechanism of how the compounds achieve potent inhibition remained incompletely understood. We now show that the activity of ARS-853 and ARS-1620 is primarily driven by KRAS-mediated catalysis of the chemical reaction with Cys12 in human KRAS, while the reversible binding affinity is weak, in the hundreds of micromolar or higher range. The mechanism resolves how an induced, shallow and dynamic pocket not expected to support high-affinity binding of small molecules can nevertheless be targeted with potent inhibitors and may be applicable to other targets conventionally considered undruggable.

PubMed: 29760531
DOI: 10.1038/s41594-018-0061-5

Experimental method

X-RAY DIFFRACTION (1.43 Å)