5JHA

Structure of Phosphoinositide 3-kinase gamma (PI3K) bound to the potent inhibitor PIKin2

5JHA の概要

• エントリーDOI: 10.2210/pdb5jha/pdb
• 分子名称: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, [1-{4-[6-amino-4-(trifluoromethyl)pyridin-3-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}-3-(chloromethyl)azetidin-3-yl]methanol, SULFATE ION, ... (4 entities in total)
• 機能のキーワード: inhibitor, lipid kinase, pi3k, transferase
• 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: 110741.32

構造登録者

Burke, J.E.,Inglis, A.J.,Williams, R.L. (登録日: 2016-04-20, 公開日: 2017-03-15, 最終更新日: 2024-01-10)

主引用文献

Bohnacker, T.,Prota, A.E.,Beaufils, F.,Burke, J.E.,Melone, A.,Inglis, A.J.,Rageot, D.,Sele, A.M.,Cmiljanovic, V.,Cmiljanovic, N.,Bargsten, K.,Aher, A.,Akhmanova, A.,Diaz, J.F.,Fabbro, D.,Zvelebil, M.,Williams, R.L.,Steinmetz, M.O.,Wymann, M.P.
Deconvolution of Buparlisib's mechanism of action defines specific PI3K and tubulin inhibitors for therapeutic intervention.
Nat Commun, 8:14683-14683, 2017

PubMed Abstract: BKM120 (Buparlisib) is one of the most advanced phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of cancer, but it interferes as an off-target effect with microtubule polymerization. Here, we developed two chemical derivatives that differ from BKM120 by only one atom. We show that these minute changes separate the dual activity of BKM120 into discrete PI3K and tubulin inhibitors. Analysis of the compounds cellular growth arrest phenotypes and microtubule dynamics suggest that the antiproliferative activity of BKM120 is mainly due to microtubule-dependent cytotoxicity rather than through inhibition of PI3K. Crystal structures of BKM120 and derivatives in complex with tubulin and PI3K provide insights into the selective mode of action of this class of drugs. Our results raise concerns over BKM120's generally accepted mode of action, and provide a unique mechanistic basis for next-generation PI3K inhibitors with improved safety profiles and flexibility for use in combination therapies.

PubMed: 28276440
DOI: 10.1038/ncomms14683

実験手法

X-RAY DIFFRACTION (2.51 Å)