Discovery of a Phosphoinositide 3-Kinase (PI3K) β/δ Inhibitor for the Treatment of Phosphatase and Tensin Homolog (PTEN) Deficient Tumors: Building PI3Kβ Potency in a PI3Kδ-Selective Template by Targeting Nonconserved Asp856

  • J Med Chem. 2017 Feb 23;60(4):1555-1567. doi: 10.1021/acs.jmedchem.6b01821.
Stephane Perreault  1 ,  Jayaraman Chandrasekhar  1 ,  Zhi-Hua Cui  1 ,  Jerry Evarts  1 ,  Jia Hao  2 ,  Joshua A Kaplan  2 ,  Adam Kashishian  1 ,  Kathleen S Keegan  1 ,  Thomas Kenney  1 ,  David Koditek  2 ,  Latesh Lad  2 ,  Eve-Irene Lepist  2 ,  Mary E McGrath  2 ,  Leena Patel  1 ,  Bart Phillips  2 ,  Joseph Therrien  1 ,  Jennifer Treiberg  1 ,  Anella Yahiaoui  1 ,  Gary Phillips  1
Affiliations
  • 1. Gilead Sciences, Inc. , 199 E. Blaine Street, Seattle, Washington 98102, United States.
  • 2. Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
PMID: 28106991 DOI: 10.1021/acs.jmedchem.6b01821
Abstract

Phosphoinositide 3-kinase (PI3K) β signaling is required to sustain Cancer cell growth in which the tumor suppressor Phosphatase and tensin homolog (PTEN) has been deactivated. This manuscript describes the discovery, optimization, and in vivo evaluation of a novel series of PI3Kβ/δ inhibitors in which PI3Kβ potency was built in a PI3Kδ-selective template. This work led to the discovery of a highly selective PI3Kβ/δ inhibitor displaying excellent pharmacokinetic profile and efficacy in a human PTEN-deficient LNCaP prostate carcinoma xenograft tumor model.

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