4DK5

Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine inhibitor

Summary for 4DK5

• Entry DOI: 10.2210/pdb4dk5/pdb
• Descriptor: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 4-(2-[(6-methoxypyridin-3-yl)amino]-5-{[4-(methylsulfonyl)piperazin-1-yl]methyl}pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine, ... (4 entities in total)
• Functional Keywords: phosphotransferase, cancer, p85-alpha, p85-beta, ras, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P48736
• Total number of polymer chains: 1
• Total formula weight: 110540.75

Authors

Whittington, D.A.,Tang, J.,Yakowec, P. (deposition date: 2012-02-03, release date: 2012-05-16, Last modification date: 2023-09-13)

Primary citation

Smith, A.L.,D'Angelo, N.D.,Bo, Y.Y.,Booker, S.K.,Cee, V.J.,Herberich, B.,Hong, F.T.,Jackson, C.L.,Lanman, B.A.,Liu, L.,Nishimura, N.,Pettus, L.H.,Reed, A.B.,Tadesse, S.,Tamayo, N.A.,Wurz, R.P.,Yang, K.,Andrews, K.L.,Whittington, D.A.,McCarter, J.D.,Miguel, T.S.,Zalameda, L.,Jiang, J.,Subramanian, R.,Mullady, E.L.,Caenepeel, S.,Freeman, D.J.,Wang, L.,Zhang, N.,Wu, T.,Hughes, P.E.,Norman, M.H.
Structure-based design of a novel series of potent, selective inhibitors of the class I phosphatidylinositol 3-kinases.
J.Med.Chem., 55:5188-5219, 2012

PubMed Abstract: A highly selective series of inhibitors of the class I phosphatidylinositol 3-kinases (PI3Ks) has been designed and synthesized. Starting from the dual PI3K/mTOR inhibitor 5, a structure-based approach was used to improve potency and selectivity, resulting in the identification of 54 as a potent inhibitor of the class I PI3Ks with excellent selectivity over mTOR, related phosphatidylinositol kinases, and a broad panel of protein kinases. Compound 54 demonstrated a robust PD-PK relationship inhibiting the PI3K/Akt pathway in vivo in a mouse model, and it potently inhibited tumor growth in a U-87 MG xenograft model with an activated PI3K/Akt pathway.

PubMed: 22548365
DOI: 10.1021/jm300184s

Experimental method

X-RAY DIFFRACTION (2.95 Å)