3NZS

Structure-based Optimization of Pyrazolo -Pyrimidine and -Pyridine Inhibitors of PI3-Kinase

Summary for 3NZS

• Entry DOI: 10.2210/pdb3nzs/pdb
• Related: 3NZU
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, 6-(1,1-dioxidothiomorpholin-4-yl)-N-(3-methoxyphenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2 entities in total)
• Functional Keywords: kinase p110, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 109770.06

Authors

Murray, J.M.,Wiesmann, C. (deposition date: 2010-07-16, release date: 2010-12-29, Last modification date: 2024-02-21)

Primary citation

Staben, S.T.,Heffron, T.P.,Sutherlin, D.P.,Bhat, S.R.,Castanedo, G.M.,Chuckowree, I.S.,Dotson, J.,Folkes, A.J.,Friedman, L.S.,Lee, L.,Lesnick, J.,Lewis, C.,Murray, J.M.,Nonomiya, J.,Olivero, A.G.,Plise, E.,Pang, J.,Prior, W.W.,Salphati, L.,Rouge, L.,Sampath, D.,Tsui, V.,Wan, N.C.,Wang, S.,Wiesmann, C.,Wu, P.,Zhu, B.Y.
Structure-based optimization of pyrazolo-pyrimidine and -pyridine inhibitors of PI3-kinase.
Bioorg.Med.Chem.Lett., 20:6048-6051, 2010

PubMed Abstract: Starting from HTS hit 1a, X-ray co-crystallization and molecular modeling were used to design potent and selective inhibitors of PI3-kinase. Bioavailablity in this series was improved through careful modulation of physicochemical properties. Compound 12 displayed in vivo knockdown of PI3K pharmacodynamic markers such as pAKT, pPRAS40, and pS6RP in a PC3 prostate cancer xenograft model.

PubMed: 20822905
DOI: 10.1016/j.bmcl.2010.08.067

Experimental method

X-RAY DIFFRACTION (2.75 Å)