Design and development of a macrocyclic series targeting phosphoinositide 3-kinase δ

DOI: 10.1021/acsmedchemlett.0c00061

Authors: Jonathan A. Spencer (GSK Medicines Research Centre; University of Strathclyde) , Ian R. Baldwin (GSK Medicines Research Centre) , Nick Barton (GSK Medicines Research Centre) , Chun-Wa Chung (GSK Medicines Research Centre) , Máire A. Convery (GSK Medicines Research Centre) , Christopher D. Edwards (GSK Medicines Research Centre) , Craig Jamieson (University of Strathclyde) , David N. Mallett (GSK Medicines Research Centre) , James E. Rowedder (GSK Medicines Research Centre) , Paul Rowland (GSK Medicines Research Centre) , Daniel A. Thomas (GSK Medicines Research Centre) , Charlotte J. Hardy (GSK Medicines Research Centre)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acs Medicinal Chemistry Letters , VOL 11 , PAGES 1386 - 1391

State: Published (Approved)
Published: July 2020

Abstract: A macrocyclization approach has been explored on a series of benzoxazine phosphoinositide 3-kinase δ inhibitors, resulting in compounds with improved potency, permeability, and in vivo clearance while maintaining good solubility. The thermodynamics of binding was explored via surface plasmon resonance, and the binding of lead macrocycle 19 was found to be almost exclusively entropically driven compared with progenitor 18, which demonstrated both enthalpic and entropic contributions. The pharmacokinetics of macrocycle 19 was also explored in vivo, where it showed reduced clearance when compared with the progenitor 18. This work adds to the growing body of evidence that macrocyclization could provide an alternative and complementary approach to the design of small-molecule inhibitors, with the potential to deliver differentiated properties.

Journal Keywords: Macrocycle; PI3Kδ; Thermodynamics; Lipid kinase

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


Instruments: I04-Macromolecular Crystallography

Added On: 29/07/2020 09:55

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)