Design of Selective Benzoxazepin PI3Kδ Inhibitors Through Control of Dihedral Angles
journal contribution
posted on 2017-08-25, 00:00 authored by Brian S. Safina, Richard L. Elliott, Andrew K. Forrest, Robert A. Heald, Jeremy M. Murray, Jim Nonomiya, Jodie Pang, Laurent Salphati, Eileen M. Seward, Steven T. Staben, Mark Ultsch, Binqing Wei, Wenqian Yang, Daniel P. SutherlinA novel selective benzoxazepin inhibitor
of PI3Kδ has been discovered. Beginning from compound 3, an αPI3K inhibitor, we utilized structure-based drug
design and computational analysis of dihedral torsion angles to optimize
for PI3Kδ isoform potency and isoform selectivity. Further medicinal
chemistry optimization of the series led to the identification of 24, a highly potent and selective inhibitor of PI3Kδ.
