6PGO

Crystal structure of human KRAS G12C covalently bound to a phthalazine inhibitor

Summary for 6PGO

• Entry DOI: 10.2210/pdb6pgo/pdb
• Descriptor: GTPase KRas, MAGNESIUM ION, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: inhibitor, gtpase, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 43994.15

Authors

Mohr, C. (deposition date: 2019-06-24, release date: 2019-12-25, Last modification date: 2024-11-20)

Primary citation

Lanman, B.A.,Allen, J.R.,Allen, J.G.,Amegadzie, A.K.,Ashton, K.S.,Booker, S.K.,Chen, J.J.,Chen, N.,Frohn, M.J.,Goodman, G.,Kopecky, D.J.,Liu, L.,Lopez, P.,Low, J.D.,Ma, V.,Minatti, A.E.,Nguyen, T.T.,Nishimura, N.,Pickrell, A.J.,Reed, A.B.,Shin, Y.,Siegmund, A.C.,Tamayo, N.A.,Tegley, C.M.,Walton, M.C.,Wang, H.L.,Wurz, R.P.,Xue, M.,Yang, K.C.,Achanta, P.,Bartberger, M.D.,Canon, J.,Hollis, L.S.,McCarter, J.D.,Mohr, C.,Rex, K.,Saiki, A.Y.,San Miguel, T.,Volak, L.P.,Wang, K.H.,Whittington, D.A.,Zech, S.G.,Lipford, J.R.,Cee, V.J.
Discovery of a Covalent Inhibitor of KRASG12C(AMG 510) for the Treatment of Solid Tumors.
J.Med.Chem., 63:52-65, 2020

PubMed Abstract: KRAS has emerged as a promising target in the treatment of solid tumors. Covalent inhibitors targeting the mutant cysteine-12 residue have been shown to disrupt signaling by this long-"undruggable" target; however clinically viable inhibitors have yet to be identified. Here, we report efforts to exploit a cryptic pocket (H95/Y96/Q99) we identified in KRAS to identify inhibitors suitable for clinical development. Structure-based design efforts leading to the identification of a novel quinazolinone scaffold are described, along with optimization efforts that overcame a configurational stability issue arising from restricted rotation about an axially chiral biaryl bond. Biopharmaceutical optimization of the resulting leads culminated in the identification of AMG 510, a highly potent, selective, and well-tolerated KRAS inhibitor currently in phase I clinical trials (NCT03600883).

PubMed: 31820981
DOI: 10.1021/acs.jmedchem.9b01180

Experimental method

X-RAY DIFFRACTION (1.6 Å)