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Structure Guided Optimization of a Fragment Hit to Imidazopyridine Inhibitors of PI3K

Pecchi, Sabina and Ni, Zhi-Jie and Han, Wooseok and Smith, Aaron and Jiong, Lan and Burger, Matthew and Merritt, Hanne and Wiesmann, Marion and Kaufman, Susan and Chan, John and Knapp, Mark and Jansen, Johanna and Hu, Kay and Voliva, Charles (2013) Structure Guided Optimization of a Fragment Hit to Imidazopyridine Inhibitors of PI3K. Bioorganic and Medicinal Chemistry Letters, 23 (16). pp. 4652-4656. ISSN 0960894X

Abstract

PI3 Kinases are a family of lipid kinases mediating numerous cell processes such as proliferation, migration and differentiation. The PI3 Kinase pathway is often de-regulated in cancer through PI3Kalpha overexpression, gene amplification, mutations and PTEN phosphatase deletion. PI3K inhibitors represent therefore an attractive therapeutic modality for cancer treatment. Herein we describe how the potency of a benzothiazole fragment hit was quickly improved based on structural information and how this early chemotype was further optimized through scaffold hopping. This effort led to the identification of a series of 2-acetamido-5-heterocyclyl imidazopyridines showing potent in vitro activity against all class I PI3Ks and attractive pharmacokinetic properties.

Item Type: Article
Date Deposited: 27 Apr 2016 23:45
Last Modified: 27 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/9324

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