5JHA

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

Summary for 5JHA

• Entry DOI: 10.2210/pdb5jha/pdb
• Descriptor: 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)
• Functional Keywords: inhibitor, lipid kinase, pi3k, transferase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 110741.32

Authors

Burke, J.E.,Inglis, A.J.,Williams, R.L. (deposition date: 2016-04-20, release date: 2017-03-15, Last modification date: 2024-01-10)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.51 Å)