4FLH

Crystal structure of human PI3K-gamma in complex with AMG511

Summary for 4FLH

• Entry DOI: 10.2210/pdb4flh/pdb
• Related: 4DK5 4F1S 4FJY 4FJZ
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform, SULFATE ION, 4-(2-[(5-fluoro-6-methoxypyridin-3-yl)amino]-5-{(1R)-1-[4-(methylsulfonyl)piperazin-1-yl]ethyl}pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine, ... (4 entities in total)
• Functional Keywords: p110, phosphotransferase, cancer, p85, phosphorylation, transferase-inhibitor complex, transferase/inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm : P48736
• Total number of polymer chains: 1
• Total formula weight: 110725.89

Authors

Whittington, D.A.,Tang, J.,Yakowec, P. (deposition date: 2012-06-14, release date: 2012-08-29, Last modification date: 2024-02-28)

Primary citation

Norman, M.H.,Andrews, K.L.,Bo, Y.Y.,Booker, S.K.,Caenepeel, S.,Cee, V.J.,D'Angelo, N.D.,Freeman, D.J.,Herberich, B.J.,Hong, F.T.,Jackson, C.L.,Jiang, J.,Lanman, B.A.,Liu, L.,McCarter, J.D.,Mullady, E.L.,Nishimura, N.,Pettus, L.H.,Reed, A.B.,Miguel, T.S.,Smith, A.L.,Stec, M.M.,Tadesse, S.,Tasker, A.,Aidasani, D.,Zhu, X.,Subramanian, R.,Tamayo, N.A.,Wang, L.,Whittington, D.A.,Wu, B.,Wu, T.,Wurz, R.P.,Yang, K.,Zalameda, L.,Zhang, N.,Hughes, P.E.
Selective Class I Phosphoinositide 3-Kinase Inhibitors: Optimization of a Series of Pyridyltriazines Leading to the Identification of a Clinical Candidate, AMG 511.
J.Med.Chem., 55:7796-7816, 2012

PubMed Abstract: The phosphoinositide 3-kinase family catalyzes the phosphorylation of phosphatidylinositol-4,5-diphosphate to phosphatidylinositol-3,4,5-triphosphate, a secondary messenger which plays a critical role in important cellular functions such as metabolism, cell growth, and cell survival. Our efforts to identify potent, efficacious, and orally available phosphatidylinositol 3-kinase (PI3K) inhibitors as potential cancer therapeutics have resulted in the discovery of 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 (1). In this paper, we describe the optimization of compound 1, which led to the design and synthesis of pyridyltriazine 31, a potent pan inhibitor of class I PI3Ks with a superior pharmacokinetic profile. Compound 31 was shown to potently block the targeted PI3K pathway in a mouse liver pharmacodynamic model and inhibit tumor growth in a U87 malignant glioma glioblastoma xenograft model. On the basis of its excellent in vivo efficacy and pharmacokinetic profile, compound 31 was selected for further evaluation as a clinical candidate and was designated AMG 511.

PubMed: 22897589
DOI: 10.1021/jm300846z

Experimental method

X-RAY DIFFRACTION (2.6 Å)