5V9U

Crystal Structure of small molecule ARS-1620 covalently bound to K-Ras G12C

Summary for 5V9U

• Entry DOI: 10.2210/pdb5v9u/pdb
• Descriptor: GTPase KRas, CALCIUM ION, (S)-1-{4-[6-chloro-8-fluoro-7-(2-fluoro-6-hydroxyphenyl)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, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 2
• Total formula weight: 41066.52

Authors

Janes, M.R.,Zhang, J.,Li, L.-S.,Hansen, R.,Peters, U.,Guo, X.,Chen, Y.,Babbar, A.,Firdaus, S.J.,Feng, J.,Chen, J.H.,Li, S.,Brehmer, D.,Darjania, L.,Li, S.,Long, Y.O.,Thach, C.,Liu, Y.,Zarieh, A.,Ely, T.,Kucharski, J.M.,Kessler, L.V.,Wu, T.,Wang, Y.,Yao, Y.,Deng, X.,Zarrinkar, P.,Dashyant, D.,Lorenzi, M.V.,Hu-Lowe, D.,Patricelli, M.P.,Ren, P.,Liu, Y. (deposition date: 2017-03-23, release date: 2018-02-07, Last modification date: 2024-10-30)

Primary citation

Janes, M.R.,Zhang, J.,Li, L.S.,Hansen, R.,Peters, U.,Guo, X.,Chen, Y.,Babbar, A.,Firdaus, S.J.,Darjania, L.,Feng, J.,Chen, J.H.,Li, S.,Li, S.,Long, Y.O.,Thach, C.,Liu, Y.,Zarieh, A.,Ely, T.,Kucharski, J.M.,Kessler, L.V.,Wu, T.,Yu, K.,Wang, Y.,Yao, Y.,Deng, X.,Zarrinkar, P.P.,Brehmer, D.,Dhanak, D.,Lorenzi, M.V.,Hu-Lowe, D.,Patricelli, M.P.,Ren, P.,Liu, Y.
Targeting KRAS Mutant Cancers with a Covalent G12C-Specific Inhibitor.
Cell, 172:578-589.e17, 2018

PubMed Abstract: KRAS was recently identified to be potentially druggable by allele-specific covalent targeting of Cys-12 in vicinity to an inducible allosteric switch II pocket (S-IIP). Success of this approach requires active cycling of KRAS between its active-GTP and inactive-GDP conformations as accessibility of the S-IIP is restricted only to the GDP-bound state. This strategy proved feasible for inhibiting mutant KRAS in vitro; however, it is uncertain whether this approach would translate to in vivo. Here, we describe structure-based design and identification of ARS-1620, a covalent compound with high potency and selectivity for KRAS. ARS-1620 achieves rapid and sustained in vivo target occupancy to induce tumor regression. We use ARS-1620 to dissect oncogenic KRAS dependency and demonstrate that monolayer culture formats significantly underestimate KRAS dependency in vivo. This study provides in vivo evidence that mutant KRAS can be selectively targeted and reveals ARS-1620 as representing a new generation of KRAS-specific inhibitors with promising therapeutic potential.

PubMed: 29373830
DOI: 10.1016/j.cell.2018.01.006

Experimental method

X-RAY DIFFRACTION (1.38 Å)