8TDU

STX-478, a Mutant-Selective, Allosteric Inhibitor bound to PI3Kalpha

8TDU の概要

• エントリーDOI: 10.2210/pdb8tdu/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, N~2~-{(4S,11aP)-2-[(4S)-4-(difluoromethyl)-2-oxo-1,3-oxazolidin-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl}-L-alaninamide, ... (5 entities in total)
• 機能のキーワード: kinase, inhibitor, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 320910.84

構造登録者

Hilbert, B.J.,Brooijmans, N.,Buckbinder, L.,St.Jean Jr., D.J. (登録日: 2023-07-05, 公開日: 2023-09-06, 最終更新日: 2023-11-08)

主引用文献

Buckbinder, L.,St Jean Jr., D.J.,Tieu, T.,Ladd, B.,Hilbert, B.,Wang, W.,Alltucker, J.T.,Manimala, S.,Kryukov, G.V.,Brooijmans, N.,Dowdell, G.,Jonsson, P.,Huff, M.,Guzman-Perez, A.,Jackson, E.L.,Goncalves, M.D.,Stuart, D.D.
STX-478, a Mutant-Selective, Allosteric PI3K alpha Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3K alpha-Mutant Xenografts.
Cancer Discov, 13:2432-2447, 2023

PubMed Abstract: Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.

PubMed: 37623743
DOI: 10.1158/2159-8290.CD-23-0396

実験手法

X-RAY DIFFRACTION (3.11 Å)