jm1c01102_si_001.pdf (623.47 kB)
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode
journal contribution
posted on 2021-09-11, 13:03 authored by Kenneth Down, Augustin Amour, Niall A. Anderson, Nick Barton, Sebastien Campos, Edward P. Cannons, Cole Clissold, Maire A. Convery, John J. Coward, Kevin Doyle, Birgit Duempelfeld, Christopher D. Edwards, Michael D. Goldsmith, Jana Krause, David N. Mallett, Grant A. McGonagle, Vipulkumar K. Patel, James Rowedder, Paul Rowland, Andrew Sharpe, Srividya Sriskantharajah, Daniel A. Thomas, Douglas W. Thomson, Sorif Uddin, J. Nicole Hamblin, Edith M. HesselOptimization of a previously reported
lead series of PI3Kδ
inhibitors with a novel binding mode led to the identification of
a clinical candidate compound 31 (GSK251). Removal of
an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide
followed by locating an interaction with Trp760 led to a highly selective
compound 9. Further optimization to avoid glutathione
trapping, to enhance potency and selectivity, and to optimize an oral
pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and
a rat toxicity profile suitable for further development.
