ISDA: 9PZF

Deposition Date 2025-08-11

Release Date 2026-03-11

Last Version Date 2026-03-25

Entry Detail

PDB ID:

9PZF

Keywords:

ONCOPROTEIN

Title:

Structure of KRAS G12C bound to Compound 4

Biological Source:

Source Organism(s):

Homo sapiens (Taxon ID: 9606)

Expression System(s):

Escherichia coli

Method Details:

Experimental Method:

X-RAY DIFFRACTION

Resolution:

1.84 Å

R-Value Free:

0.20

R-Value Work:

0.16

R-Value Observed:

0.16

Space Group:

P 1

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Macromolecular Entities

Structures with similar UniProt ID

Protein Blast

Polymer Type:polypeptide(L)
Molecule:Isoform 2B of GTPase KRas
Gene (Uniprot):KRAS
Mutagens:G12C variant, C51S, C80L, C118S
Chain IDs:A, B
Chain Length:187
Number of Molecules:2
Biological Source:Homo sapiens

UniProt ID:P01116 Pfam ID:PF00071 EC:3.6.5.2

Ligand Molecules

A1CQ2

GDP

Primary Citation

Discovery and Characterization of Divarasib (GDC-6036), a Potent Covalent Inhibitor of KRAS G12C.

Endres, N.F, Do, S, Mroue, R, Terrett, J.A, Saabye, M, Oh, A, Hunsaker, T, Chan, E, Tran, J.C, Nguyen, L.K, Lian, Q, Ma, T.P, Garner, T, Gerosa, L, Beresini, M, Boudreau, A, Bronner, S.M, Cyr, P, Ishisoko, N, Izrayelit, Y, Jiang, F, Kellar, T, La, H, Labadie, S, Lardy, M, Liu, L, Liu, W, Miller, S, Rudolph, J, Plise, E, Sellers, B.D, Shao, C, Wang, W, Wang, Y, Wei, W, Wong, S, Yu, C, Yu, K, Yuen, P.W, Zang, R, Zhang, C, Zhou, Y, Zhu, X, Quinn, J.G, Ye, X, Kiefer, J.R, Mao, J, Evangelista, M, Merchant, M, Landry, M.L, Malhotra, S, Purkey, H.E.Show

J. Med. Chem. 69 5147 5165 (2026)

PMID: 41766690 DOI: 10.1021/acs.jmedchem.5c02272

Abstact

KRAS G12C is one of the most prevalent oncogenic mutations in nonsmall cell lung cancer. Herein we describe the discovery and optimization of divarasib (GDC-6036), an orally available, highly potent, and selective covalent KRAS G12C inhibitor. We demonstrate a significant noncovalent binding component of divarasib that contributes to its potency and rapid kinetics. Divarasib has greater potency and kinetics of alkylation compared with other KRAS G12C inhibitors in vitro and shows robust tumor growth inhibition in multiple KRAS G12C-positive cell lines.

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Primary Citation of related structures

Abstact

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