8V8H

PI3Ka H1047R co-crystal structure with inhibitor in cryptic pocket near H1047R (compound 4).

8V8H の概要

• エントリーDOI: 10.2210/pdb8v8h/pdb
• 関連するPDBエントリー: 8V8I 8V8J 8V8U 8V8V
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 2-({(1R)-1-[2-(4,4-dimethylpiperidin-1-yl)-3,6-dimethyl-4-oxo-4H-1-benzopyran-8-yl]ethyl}amino)benzoic acid, ... (4 entities in total)
• 機能のキーワード: h1047r, pi3k, pi3ka, signaling protein
• 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: 318638.93

構造登録者

Gunn, R.J.,Lawson, J.D. (登録日: 2023-12-05, 公開日: 2024-03-20, 最終更新日: 2024-04-10)

主引用文献

Ketcham, J.M.,Harwood, S.J.,Aranda, R.,Aloiau, A.N.,Bobek, B.M.,Briere, D.M.,Burns, A.C.,Caddell Haatveit, K.,Calinisan, A.,Clarine, J.,Elliott, A.,Engstrom, L.D.,Gunn, R.J.,Ivetac, A.,Jones, B.,Kuehler, J.,Lawson, J.D.,Nguyen, N.,Parker, C.,Pearson, K.E.,Rahbaek, L.,Saechao, B.,Wang, X.,Waters, A.,Waters, L.,Watkins, A.H.,Olson, P.,Smith, C.R.,Christensen, J.G.,Marx, M.A.
Discovery of Pyridopyrimidinones that Selectively Inhibit the H1047R PI3K alpha Mutant Protein.
J.Med.Chem., 67:4936-4949, 2024

PubMed Abstract: The H1047R mutation of is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3Kα over PI3Kα is crucial due to the role that PI3Kα plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3Kα-selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3Kα with high selectivity over PI3Kα, resulting in the discovery of compound . When dosed in the HCC1954 tumor model in mice, provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3Kα including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

PubMed: 38477582
DOI: 10.1021/acs.jmedchem.4c00078

実験手法

X-RAY DIFFRACTION (3.58 Å)