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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.


Hengmiao Cheng, Suvi T M Orr, Simon Bailey, Alexei Brooun, Ping Chen, Judith G Deal, Yali L Deng, Martin P Edwards, Gary M Gallego, Neil Grodsky, Buwen Huang, Mehran Jalaie, Stephen Kaiser, Robert S Kania, Susan E Kephart, Jennifer Lafontaine, Martha A Ornelas, Mason Pairish, Simon Planken, Hong Shen, Scott Sutton, Luke Zehnder, Chau D Almaden, Shubha Bagrodia, Matthew D Falk, Hovhannes J Gukasyan, Caroline Ho, Xiaolin Kang, Rachel E Kosa, Ling Liu, Mary E Spilker, Sergei Timofeevski, Ravi Visswanathan, Zhenxiong Wang, Fanxiu Meng, Shijian Ren, Li Shao, Feng Xu, John C Kath. Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195). Journal of medicinal chemistry. 2021 Jan 14;64(1):644-661

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PMID: 33356246

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