2. Academic Validation
  3. Discovery of an Atropisomeric PI3Kβ Selective Inhibitor through Optimization of the Hinge Binding Motif

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

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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-145338
    PI3Kβ抑制剂
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