4J6I

Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase beta isoform

4J6I の概要

• エントリーDOI: 10.2210/pdb4j6i/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 2-methyl-1-(4-{2-[1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl]-4,5-dihydro[1]benzoxepino[5,4-d][1,3]thiazol-8-yl}-1H-pyrazol-1-yl)propan-2-ol (2 entities in total)
• 機能のキーワード: beta-sparing, sbdd, catalytic subunit gamma, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm: P48736
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 111217.60

構造登録者

Murray, J.M.,Rouge, L.,Wu, P. (登録日: 2013-02-11, 公開日: 2013-08-28, 最終更新日: 2024-02-28)

主引用文献

Staben, S.T.,Ndubaku, C.,Blaquiere, N.,Belvin, M.,Bull, R.J.,Dudley, D.,Edgar, K.,Gray, D.,Heald, R.,Heffron, T.P.,Jones, G.E.,Jones, M.,Kolesnikov, A.,Lee, L.,Lesnick, J.,Lewis, C.,Murray, J.,McLean, N.J.,Nonomiya, J.,Olivero, A.G.,Ord, R.,Pang, J.,Price, S.,Prior, W.W.,Rouge, L.,Salphati, L.,Sampath, D.,Wallin, J.,Wang, L.,Wei, B.,Weismann, C.,Wu, P.
Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase beta isoform.
Bioorg.Med.Chem.Lett., 23:2606-2613, 2013

PubMed Abstract: A series of suitable five-membered heterocyclic alternatives to thiophenes within a thienobenzoxepin class of PI3-kinase (PI3K) inhibitors was discovered. Specific thiazolobenzoxepin 8-substitution was identified that increased selectivity over PI3Kβ. PI3Kβ-sparing compound 27 (PI3Kβ Ki,app/PI3Kα Ki,app=57) demonstrated dose-dependent knockdown of pAKT, pPRAS40 and pS6RP in vivo as well as differential effects in an in vitro proliferation cell line screen compared to pan PI3K inhibitor GDC-0941. A new structure-based hypothesis for reducing inhibition of the PI3K β isoform while maintaining activity against α, δ and γ isoforms is presented.

PubMed: 23540645
DOI: 10.1016/j.bmcl.2013.02.102

実験手法

X-RAY DIFFRACTION (2.9 Å)