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

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 <b>38</b> (BEN-28010) as a freely brain-penetrant, potent, and selective CHK1 inhibitor, derived from virtual screening hit <b>1</b>. <i>In vivo</i> pharmacological studies demonstrated efficacy of orally administered <b>38</b> 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, <b>38</b> utilizes an underrepresented aminoimidazole kinase hinge-binding motif that may have broader utility within kinase inhibitor drug discovery.