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: 2025-11-26)

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.,Lu, J.,Pastuszka, M.K.,Pollock, J.,Sigler, J.J.,Tomaschko, M.,Tran, E.,Yue, C.,Kinsella, T.M.,Molina-Arcas, M.,Cook, B.N.,Simon, G.M.,Weinstein, D.S.,Downward, J.,Patricelli, M.P.
Covalent inhibitors of the PI3K alpha RAS binding domain impair tumor growth driven by RAS and HER2.
Science, 390:702-709, 2025

PubMed Abstract: Genetic disruption of the RAS binding domain (RBD) of phosphoinositide 3-kinase alpha (PI3Kα) impairs the growth of tumors driven by the small guanosine triphosphatase RAS in mice and does not affect PI3Kα's role in insulin-mediated control of glucose homeostasis. Selectively blocking the RAS-PI3Kα interaction may represent a strategy for treating RAS-dependent cancers as it avoids the toxicity associated with inhibitors of PI3Kα lipid kinase activity. We developed compounds that bind covalently to cysteine 242 in the RBD of PI3K p110α and block RAS activation of PI3Kα activity. In mice, inhibitors slow the growth of RAS mutant tumors and human epidermal growth factor receptor 2-overexpressing tumors, particularly when combined with other inhibitors of the RAS/mitogen-activated protein kinase pathway, without causing hyperglycemia.

PubMed: 41066541
DOI: 10.1126/science.adv2684

Experimental method

X-RAY DIFFRACTION (2.827 Å)