Optimization of Orally Bioavailable PI3Kδ Inhibitors and Identification of Vps34 as a Key Selectivity Target
dataset
posted on 2020-01-08, 15:33 authored by Zoë A. Henley, Augustin Amour, Nick Barton, Marcus Bantscheff, Giovanna Bergamini, Sophie M. Bertrand, Máire Convery, Kenneth Down, Birgit Dümpelfeld, Chris D. Edwards, Paola Grandi, Paul M. Gore, Steve Keeling, Stefano Livia, David Mallett, Aoife Maxwell, Mark Price, Christina Rau, Friedrich B. M. Reinhard, James Rowedder, Paul Rowland, Jonathan A. Taylor, Daniel A. Thomas, Edith M. Hessel, J. Nicole HamblinOptimization
of a lead series of PI3Kδ inhibitors based on
a dihydroisobenzofuran core led to the identification of potent, orally
bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kδ,
and compound 19 was not well-tolerated in a 7-day rat
toxicity study. Structure-based design led to an improvement in selectivity
for PI3Kδ over Vps34 and, a focus on oral phramacokinetics properties
resulted in the discovery of compound 41, which showed
improved toxicological outcomes at similar exposure levels to compound 19.
