4J6I

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

Summary for 4J6I

• Entry DOI: 10.2210/pdb4j6i/pdb
• Descriptor: 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)
• Functional Keywords: beta-sparing, sbdd, catalytic subunit gamma, phosphorylation, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 111217.60

Authors

Murray, J.M.,Rouge, L.,Wu, P. (deposition date: 2013-02-11, release date: 2013-08-28, Last modification date: 2024-02-28)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.9 Å)