Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif
Stéphane Perreault, Fatima Arjmand, Jayaraman Chandrasekhar, Hao Jia, Kathleen S. Keegan, David Koditek, Eve‐Irene Lepist, Clinton K. Matson, Mary E. McGrath, Leena Patel, Kassandra Sedillo, Joseph Therrien, Nicholas A. Till, Adrian Tomkinson, Jennifer Treiberg, Yelena Zherebina, Gary B. Phillips
Abstract
A series of PI3Kβ selective inhibitors derived from a novel 4-(1H-benzo[d]imidazol-1-yl)quinoline chemotype has been rationally designed. Crucial to achieving the desired selectivity over the other class I PI3K isoforms, including the challenging δ-isoform, was the identification of a subset of substituted pyridine hinge binders. This work led to the discovery of (P)-14, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in addition to great cellular potency in various PTEN-deficient tumor cell lines. Results from a dog toxicology study revealing structure-related, off-target ocular toxicity are also briefly discussed.