Discovery of BBI-355, a Potent, Selective, and Orally Available Checkpoint Kinase 1 Inhibitor for the Treatment of Extrachromosomal DNA Oncogene-Amplified Cancers.
Jul 2026· Journal of Medicinal Chemistry· Vol 69, pp. 17814-17824· 0 citations· 9 references
Medicine
TL;DR
BBI-355, a potent, selective, and orally available CHK1 inhibitor, demonstrates strong antitumor activity when dosed orally in mouse xenograft models, achieving regressions both as a single agent and in combination with targeted therapies.
Abstract
Checkpoint kinase 1 (CHK1), a master regulator of replication stress, has been investigated as a potential therapeutic target for over two decades. More recently, CHK1 has been implicated as a target for the treatment of ecDNA-driven, oncogene-amplified cancers. However, clinical-stage CHK1 inhibitors have historically faced challenges related to dosing schedule, tolerability, and clinical efficacy, although recent studies suggest that biomarker-driven approaches and alternative dosing strategies may address some of these limitations. Structure-guided optimization led to the discovery of BBI-355, a potent, selective, and orally available CHK1 inhibitor. BBI-355 demonstrates strong antitumor activity when dosed orally in mouse xenograft models, achieving regressions both as a single agent and in combination with targeted therapies. BBI-355 also displays favorable ADMET and PK properties and has been advanced to a clinical trial for patients with oncogene amplified cancers.
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