Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.
Basic Information
ID: ALA4616704
Journal: ACS Med Chem Lett
Title: Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.
Authors: Perreault S, Arjmand F, Chandrasekhar J, Hao J, Keegan KS, Koditek D, Lepist EI, Matson CK, McGrath ME, Patel L, Sedillo K, Therrien J, Till NA, Tomkinson A, Treiberg J, Zherebina Y, Phillips G.
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.
CiteXplore: 32551006
DOI: 10.1021/acsmedchemlett.0c00095
Patent ID: ┄