Structure-Based Drug Design and Synthesis of PI3Kα-Selective Inhibitor (PF-06843195)

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.