Discovery of a Potent, Selective, and Brain-Penetrant Checkpoint Kinase 1 Inhibitor, BEN-28010, for the Treatment of Glioblastoma

  • J Med Chem. 2025 May 8;68(9):9101-9125. doi: 10.1021/acs.jmedchem.5c00279.
Michael J Rawling  1 ,  Arpita Ray-Sinha  2 ,  Michael Bestwick  1 ,  Michael K Carter  2 ,  Sandeep K Chahal  3 ,  Anthony J Chalmers  3 ,  David J Elsey  2 ,  Amanda Giddings  2 ,  Jennie Gold  1 ,  Scott H Henderson  1 ,  Calum MacGregor  2 ,  Andrew Malcolm  1 ,  Fernando Ortega  1 ,  Anne Phelan  1 ,  Edward D Savory  1 ,  Alejandro C Schwartz  1 ,  Neil G Stevenson  1 ,  Emma L Turner  1 ,  Márton Vass  2 ,  Jamie A Wright  1 ,  Christine Watson  1
Affiliations
  • 1. BenevolentAI, Minerva Building, Babraham Research Campus, Cambridge CB22 3AT, U.K.
  • 2. BenevolentAI, 4-8 Maple Street, London W1T 5HD, U.K.
  • 3. School of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, U.K.
PMID: 40273287 DOI: 10.1021/acs.jmedchem.5c00279
Abstract

Glioblastoma (GBM) patients face a dire prognosis and alternative therapeutic options are desperately needed. Inhibition of checkpoint kinase 1 (Chk1) represents a potential therapeutic strategy for GBM through regulation of the DNA damage response (DDR) pathway, but no suitable brain-penetrant Chk1 inhibitors have been reported to date. In this study, we disclose the discovery and optimization of clinical candidate 38 (BEN-28010) as a freely brain-penetrant, potent, and selective Chk1 Inhibitor, derived from virtual screening hit 1. In vivo pharmacological studies demonstrated efficacy of orally administered 38 in several GBM CDX and PDX models as a monotherapy and in combination with ionizing radiation, including improved overall survival in an intracranially implanted GBM PDX mouse model. Additionally, 38 utilizes an underrepresented aminoimidazole kinase hinge-binding motif that may have broader utility within kinase inhibitor drug discovery.

Products