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

  • ACS Med Chem Lett. 2020 Apr 13;11(6):1236-1243. doi: 10.1021/acsmedchemlett.0c00095.
Stephane Perreault  1 ,  Fatima Arjmand  2 ,  Jayaraman Chandrasekhar  1 ,  Jia Hao  1 ,  Kathleen S Keegan  1 ,  David Koditek  2 ,  Eve-Irene Lepist  1 ,  Clinton K Matson  1 ,  Mary E McGrath  2 ,  Leena Patel  1 ,  Kassandra Sedillo  1 ,  Joseph Therrien  1 ,  Nicholas A Till  1 ,  Adrian Tomkinson  2 ,  Jennifer Treiberg  1 ,  Yelena Zherebina  2 ,  Gary Phillips  1
Affiliations
  • 1. Gilead Sciences, Inc., 199 East Blaine Street, Seattle, Washington 98102, United States.
  • 2. Gilead Sciences, Inc., 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 32551006 DOI: 10.1021/acsmedchemlett.0c00095
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.

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