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

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

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.

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