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Discovery of GSK251: A highly potent, highly selective, orally bioavailable inhibitor of PI3KΔ with a novel binding mode

DOI: 10.1021/acs.jmedchem.1c01102 DOI Help

Authors: Kenneth Down (GlaxoSmithKline R&D) , Augustin Amour (GlaxoSmithKline R&D) , Niall A. Anderson (GlaxoSmithKline R&D) , Nick Barton (GlaxoSmithKline R&D) , Sebastien Campos (GlaxoSmithKline R&D) , Edward P. Cannons (GlaxoSmithKline R&D) , Cole Clissold (Charles River Discovery) , Maire A. Convery (GlaxoSmithKline R&D) , John J. Coward (GlaxoSmithKline R&D) , Kevin Doyle (Charles River Discovery) , Birgit Duempelfeld (Cellzome GmbH) , Christopher D. Edwards (GlaxoSmithKline R&D) , Michael D. Goldsmith (Charles River Discovery) , Jana Krause (Cellzome GmbH) , David N. Mallett (GlaxoSmithKline R&D) , Grant A. Mcgonagle (GlaxoSmithKline R&D) , Vipulkumar K. Patel (GlaxoSmithKline R&D) , James Rowedder (GlaxoSmithKline R&D) , Paul Rowland (GlaxoSmithKline R&D) , Andrew Sharpe (Charles River Discovery) , Srividya Sriskantharajah (GlaxoSmithKline R&D) , Daniel A. Thomas (GlaxoSmithKline R&D) , Douglas W. Thomson (Cellzome GmbH) , Sorif Uddin (GlaxoSmithKline R&D) , J. Nicole Hamblin (GlaxoSmithKline R&D) , Edith M. Hessel (GlaxoSmithKline R&D)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 64 , PAGES 13780 - 13792

State: Published (Approved)
Published: September 2021

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.

Journal Keywords: Anatomy; Amines; Assays; Rodent models; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography

Added On: 29/09/2021 08:58

Discipline Tags:

Organic Chemistry Life Sciences & Biotech Health & Wellbeing Drug Discovery Structural biology Chemistry Biochemistry

Technical Tags:

Diffraction Macromolecular Crystallography (MX)