2. Academic Validation
  3. Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode

Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode

  • J Med Chem. 2021 Sep 23;64(18):13780-13792. doi: 10.1021/acs.jmedchem.1c01102.
Kenneth Down 1,  Augustin Amour 1,  Niall A Anderson 1,  Nick Barton 1,  Sebastien Campos 1,  Edward P Cannons 1,  Cole Clissold 2,  Maire A Convery 1,  John J Coward 1,  Kevin Doyle 2,  Birgit Duempelfeld 3,  Christopher D Edwards 1,  Michael D Goldsmith 2,  Jana Krause 3,  David N Mallett 1,  Grant A McGonagle 1,  Vipulkumar K Patel 1,  James Rowedder 1,  Paul Rowland 1,  Andrew Sharpe 2,  Srividya Sriskantharajah 1,  Daniel A Thomas 1,  Douglas W Thomson 3,  Sorif Uddin 1,  J Nicole Hamblin 1,  Edith M Hessel 1
Affiliations

Affiliations

  • 1 Medicines Research Centre, GlaxoSmithKline R&D, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
  • 2 Charles River Discovery, Chesterford Research Park, Saffron Walden CB10 1XL, U.K.
  • 3 Cellzome GmbH, A GlaxoSmithKline Company, Meyerhofstraße 1, Heidelberg 69117, Germany.
PMID: 34510892 DOI: 10.1021/acs.jmedchem.1c01102
Abstract

Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-132880
    99.88%, PI3K Inhibitor