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Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.

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.

SUBMITTER: Perreault S

PROVIDER: S-EPMC7294712 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif.

Perreault Stephane S Arjmand Fatima F Chandrasekhar Jayaraman J Hao Jia J Keegan Kathleen S KS Koditek David D Lepist Eve-Irene EI Matson Clinton K CK McGrath Mary E ME Patel Leena L Sedillo Kassandra K Therrien Joseph J Till Nicholas A NA Tomkinson Adrian A Treiberg Jennifer J Zherebina Yelena Y Phillips Gary G

ACS medicinal chemistry letters 20200413 6

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 (<i>P</i>)-<b>14</b>, a highly selective and orally bioavailable PI3Kβ inhibitor displaying an excellent pharmacokinetic profile in ad ...[more]

PMID: 32551006

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