| Literature DB >> 33356246 |
Hengmiao Cheng1, Suvi T M Orr1, Simon Bailey1, Alexei Brooun1, Ping Chen1, Judith G Deal1, Yali L Deng1, Martin P Edwards1, Gary M Gallego1, Neil Grodsky1, Buwen Huang1, Mehran Jalaie1, Stephen Kaiser1, Robert S Kania1, Susan E Kephart1, Jennifer Lafontaine1, Martha A Ornelas1, Mason Pairish1, Simon Planken1, Hong Shen1, Scott Sutton1, Luke Zehnder1, Chau D Almaden1, Shubha Bagrodia1, Matthew D Falk1, Hovhannes J Gukasyan1, Caroline Ho1, Xiaolin Kang1, Rachel E Kosa1, Ling Liu1, Mary E Spilker1, Sergei Timofeevski1, Ravi Visswanathan1, Zhenxiong Wang1, Fanxiu Meng2, Shijian Ren2, Li Shao2, Feng Xu2, John C Kath1.
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.Entities:
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Year: 2020 PMID： 33356246 DOI： 10.1021/acs.jmedchem.0c01652
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446