8TSC

Human PI3K p85alpha/p110alpha H1047R bound to compound 3

8TSC の概要

• エントリーDOI: 10.2210/pdb8tsc/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, (1S)-7-[3-fluoro-5-(trifluoromethyl)benzamido]-N-methyl-1-(2-methylphenyl)-3-oxo-2,3-dihydro-1H-isoindole-5-carboxamide (3 entities in total)
• 機能のキーワード: lipid kinase, signaling protein, signaling protein-inhibitor complex, signaling protein/inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 159305.58

構造登録者

Holliday, M.,Tang, Y.,Bulku, A.,Wilbur, J.,Fraser, J. (登録日: 2023-08-11, 公開日: 2023-11-22, 最終更新日: 2024-02-21)

主引用文献

Varkaris, A.,Pazolli, E.,Gunaydin, H.,Wang, Q.,Pierce, L.,Boezio, A.A.,Bulku, A.,DiPietro, L.,Fridrich, C.,Frost, A.,Giordanetto, F.,Hamilton, E.P.,Harris, K.,Holliday, M.,Hunter, T.L.,Iskandar, A.,Ji, Y.,Larivee, A.,LaRochelle, J.R.,Lescarbeau, A.,Llambi, F.,Lormil, B.,Mader, M.M.,Mar, B.G.,Martin, I.,McLean, T.H.,Michelsen, K.,Pechersky, Y.,Puente-Poushnejad, E.,Raynor, K.,Rogala, D.,Samadani, R.,Schram, A.M.,Shortsleeves, K.,Swaminathan, S.,Tajmir, S.,Tan, G.,Tang, Y.,Valverde, R.,Wehrenberg, B.,Wilbur, J.,Williams, B.R.,Zeng, H.,Zhang, H.,Walters, W.P.,Wolf, B.B.,Shaw, D.E.,Bergstrom, D.A.,Watters, J.,Fraser, J.S.,Fortin, P.D.,Kipp, D.R.
Discovery and Clinical Proof-of-Concept of RLY-2608, a First-in-Class Mutant-Selective Allosteric PI3K alpha Inhibitor That Decouples Antitumor Activity from Hyperinsulinemia.
Cancer Discov, 14:240-257, 2024

PubMed Abstract: PIK3CA (PI3Kα) is a lipid kinase commonly mutated in cancer, including ∼40% of hormone receptor-positive breast cancer. The most frequently observed mutants occur in the kinase and helical domains. Orthosteric PI3Kα inhibitors suffer from poor selectivity leading to undesirable side effects, most prominently hyperglycemia due to inhibition of wild-type (WT) PI3Kα. Here, we used molecular dynamics simulations and cryo-electron microscopy to identify an allosteric network that provides an explanation for how mutations favor PI3Kα activation. A DNA-encoded library screen leveraging electron microscopy-optimized constructs, differential enrichment, and an orthosteric-blocking compound led to the identification of RLY-2608, a first-in-class allosteric mutant-selective inhibitor of PI3Kα. RLY-2608 inhibited tumor growth in PIK3CA-mutant xenograft models with minimal impact on insulin, a marker of dysregulated glucose homeostasis. RLY-2608 elicited objective tumor responses in two patients diagnosed with advanced hormone receptor-positive breast cancer with kinase or helical domain PIK3CA mutations, with no observed WT PI3Kα-related toxicities.

PubMed: 37916956
DOI: 10.1158/2159-8290.CD-23-0944

実験手法

X-RAY DIFFRACTION (3.62 Å)