9E8M

Covalent inhibitor VVD-442 bound to the RAS binding domain (RBD) of PI3Ka

This is a non-PDB format compatible entry.

Summary for 9E8M

• Entry DOI: 10.2210/pdb9e8m/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, 1-[(1P)-5-bromo-2'-chloro[1,1'-biphenyl]-2-sulfonyl]-4-fluoro-N-[(2S)-4-(methanesulfonyl)butan-2-yl]piperidine-4-carboxamide (3 entities in total)
• Functional Keywords: pi3-kinase subunit alpha, pi3k-alpha, serine/threonine protein kinase pik3ca, ras binding domain, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 34819.50

Authors

Bernard, S.M.,Tamiya, J. (deposition date: 2024-11-05, release date: 2025-01-01, Last modification date: 2025-01-22)

Primary citation

Klebba, J.E.,Roy, N.,Bernard, S.M.,Grabow, S.,Hoffman, M.A.,Miao, H.,Tamiya, J.,Wang, J.,Berry, C.,Esparza-Oros, A.,Lin, R.,Liu, Y.,Pariollaud, M.,Parker, H.,Mochalkin, I.,Rana, S.,Snead, A.N.,Walton, E.J.,Wyrick, T.E.,Aitichson, E.,Bedke, K.,Brannon, J.C.,Chick, J.M.,Hee, K.,Horning, B.D.,Ismail, M.,Lamb, K.N.,Lin, W.,Metzger, J.,Pastuszka, M.K.,Pollock, J.,Sigler, J.J.,Tomaschko, M.,Tran, E.,Kinsella, T.M.,Molina-Arcas, M.,Simon, G.M.,Weinstein, D.S.,Downward, J.,Patricelli, M.P.
Covalent inhibitors of the RAS binding domain of PI3K alpha impair tumor growth driven by RAS and HER2.
Biorxiv, 2024

PubMed Abstract: Genetic disruption of the RAS binding domain (RBD) of PI 3-kinase (PI3K) prevents the growth of mutant RAS driven tumors in mice and does not impact PI3K's role in insulin mediated control of glucose homeostasis. Selectively blocking the RAS-PI3K interaction may represent an attractive strategy for treating RAS-dependent cancers as it would avoid the toxicity associated with inhibitors of PI3K lipid kinase activity such as alpelisib. Here we report compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block the ability of RAS to activate PI3K activity. These inhibitors have a profound impact on the growth of RAS mutant and also HER2 over-expressing tumors, particularly when combined with other inhibitors of the RAS/MAPK pathway, without causing hyperglycemia.

PubMed: 39763752
DOI: 10.1101/2024.12.17.629001

Experimental method

X-RAY DIFFRACTION (2.827 Å)