7K71

Crystal structure of PI3Kalpha inhibitor 4-0686

Summary for 7K71

• Entry DOI: 10.2210/pdb7k71/pdb
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, 2-(morpholin-4-yl)[4,5'-bipyrimidin]-2'-amine (2 entities in total)
• Functional Keywords: kinase, signaling protein, transferase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 110241.37

Authors

Chen, P.,Brooun, A.,Deng, Y.L.,Grodsky, N.,Kaiser, S.E. (deposition date: 2020-09-21, release date: 2021-01-06, Last modification date: 2024-04-03)

Primary citation

Cheng, H.,Orr, S.T.M.,Bailey, S.,Brooun, A.,Chen, P.,Deal, J.G.,Deng, Y.L.,Edwards, M.P.,Gallego, G.M.,Grodsky, N.,Huang, B.,Jalaie, M.,Kaiser, S.,Kania, R.S.,Kephart, S.E.,Lafontaine, J.,Ornelas, M.A.,Pairish, M.,Planken, S.,Shen, H.,Sutton, S.,Zehnder, L.,Almaden, C.D.,Bagrodia, S.,Falk, M.D.,Gukasyan, H.J.,Ho, C.,Kang, X.,Kosa, R.E.,Liu, L.,Spilker, M.E.,Timofeevski, S.,Visswanathan, R.,Wang, Z.,Meng, F.,Ren, S.,Shao, L.,Xu, F.,Kath, J.C.
Structure-Based Drug Design and Synthesis of PI3K alpha-Selective Inhibitor (PF-06843195).
J.Med.Chem., 64:644-661, 2021

PubMed Abstract: The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family. Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3)-3-{[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate ( (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of .

PubMed: 33356246
DOI: 10.1021/acs.jmedchem.0c01652

Experimental method

X-RAY DIFFRACTION (2.9 Å)