5V9L

KRAS G12C in bound to quinazoline based switch II pocket (SWIIP) binder

Summary for 5V9L

• Entry DOI: 10.2210/pdb5v9l/pdb
• Related: 5V9O
• Descriptor: GTPase KRas, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: kras mutant inhibitor, 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: 3
• Total formula weight: 60678.71

Authors

Westover, K.,Lu, J. (deposition date: 2017-03-23, release date: 2017-08-23, Last modification date: 2024-10-30)

Primary citation

Zeng, M.,Lu, J.,Li, L.,Feru, F.,Quan, C.,Gero, T.W.,Ficarro, S.B.,Xiong, Y.,Ambrogio, C.,Paranal, R.M.,Catalano, M.,Shao, J.,Wong, K.K.,Marto, J.A.,Fischer, E.S.,Janne, P.A.,Scott, D.A.,Westover, K.D.,Gray, N.S.
Potent and Selective Covalent Quinazoline Inhibitors of KRAS G12C.
Cell Chem Biol, 24:1005-1016.e3, 2017

PubMed Abstract: Targeted covalent small molecules have shown promise for cancers driven by KRAS G12C. Allosteric compounds that access an inducible pocket formed by movement of a dynamic structural element in KRAS, switch II, have been reported, but these compounds require further optimization to enable their advancement into clinical development. We demonstrate that covalent quinazoline-based switch II pocket (SIIP) compounds effectively suppress GTP loading of KRAS G12C, MAPK phosphorylation, and the growth of cancer cells harboring G12C. Notably we find that adding an amide substituent to the quinazoline scaffold allows additional interactions with KRAS G12C, and remarkably increases the labeling efficiency, potency, and selectivity of KRAS G12C inhibitors. Structural studies using X-ray crystallography reveal a new conformation of SIIP and key interactions made by substituents located at the quinazoline 2-, 4-, and 7-positions. Optimized lead compounds in the quinazoline series selectively inhibit KRAS G12C-dependent signaling and cancer cell growth at sub-micromolar concentrations.

PubMed: 28781124
DOI: 10.1016/j.chembiol.2017.06.017

Experimental method

X-RAY DIFFRACTION (1.981 Å)