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Structure-based drug design and synthesis of PI3Kα-selective inhibitor (PF-06843195)

DOI: 10.1021/acs.jmedchem.0c01652 DOI Help

Authors: Hengmiao Cheng (Pfizer Worldwide Research and Development) , Suvi T. M. Orr (Pfizer Worldwide Research and Development) , Simon Bailey (Pfizer Worldwide Research and Development) , Alexei Brooun (Pfizer Worldwide Research and Development) , Ping Chen (Pfizer Worldwide Research and Development) , Judith G. Deal (Pfizer Worldwide Research and Development) , Yali L. Deng (Pfizer Worldwide Research and Development) , Martin P. Edwards (Pfizer Worldwide Research and Development) , Gary M. Gallego (Pfizer Worldwide Research and Development) , Neil Grodsky (Pfizer Worldwide Research and Development) , Buwen Huang (Pfizer Worldwide Research and Development) , Mehran Jalaie (Pfizer Worldwide Research and Development) , Stephen Kaiser (Pfizer Worldwide Research and Development) , Robert S. Kania (Pfizer Worldwide Research and Development) , Susan E. Kephart (Pfizer Worldwide Research and Development) , Jennifer Lafontaine (Pfizer Worldwide Research and Development) , Martha A. Ornelas (Pfizer Worldwide Research and Development) , Mason Pairish (Pfizer Worldwide Research and Development) , Simon Planken (Pfizer Worldwide Research and Development) , Hong Shen (Pfizer Worldwide Research and Development) , Scott Sutton (Pfizer Worldwide Research and Development) , Luke Zehnder (Pfizer Worldwide Research and Development) , Chau D. Almaden (Pfizer Worldwide Research and Development) , Shubha Bagrodia (Pfizer Worldwide Research and Development) , Matthew D. Falk (Pfizer Worldwide Research and Development) , Hovhannes J. Gukasyan (Pfizer Worldwide Research and Development) , Caroline Ho (Pfizer Worldwide Research and Development) , Xiaolin Kang (Pfizer Worldwide Research and Development) , Rachel E. Kosa (Pfizer Worldwide Research and Development) , Ling Liu (Pfizer Worldwide Research and Development) , Mary E. Spilker (Pfizer Worldwide Research and Development) , Sergei Timofeevski (Pfizer Worldwide Research and Development) , Ravi Visswanathan (Pfizer Worldwide Research and Development) , Zhenxiong Wang (Pfizer Worldwide Research and Development) , Fanxiu Meng (Wuxi AppTec) , Shijian Ren (Wuxi AppTec) , Li Shao (Wuxi AppTec) , Feng Xu (Wuxi AppTec) , John C. Kath (Pfizer Worldwide Research and Development)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: December 2020

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 (3S)-3-{[2′-amino-5-fluoro-2-(morpholin-4-yl)-4,5′-bipyrimidin-6-yl]amino}-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (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 1.

Journal Keywords: Carbonyls; Inhibitors; Organic compounds; Peptides and proteins; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I02-Macromolecular Crystallography