Discovery of BMS-159, an Orally Active Imidazotriazine Pan-CK2 Inhibitor for the Treatment of Cancer
Year: 2026
Type: article
Abstract: Casein kinase 2 (CK2), comprising the catalytic subunits CK2α and CK2α′, is a highly conserved and constitutively active serine/threonine kinase that is implicated in oncogenic signaling and tumor maintenance, making it an attractive therapeutic target. We report a medicinal chemistry campaign that delivered an imidazotriazine pan-CK2 series culminating in BMS-135 and its phosphate prodrug BMS-159. Structure-guided design enabled a scaffold hop from imidazopyridazine to imidazotriazine that improved kinome selectivity while preserving critical hinge and Lys68 interactions. Iterative SAR optimization mitigated hERG liability by modulating distal basicity and enhanced metabolic stability via a C8 N -ethyl substitution that blocked N-dealkylation, delivering BMS-135 as a sub-nanomolar CK2 inhibitor with favorable ADMET properties and robust antitumor efficacy across xenograft and patient-derived xenograft models. Subsequent pharmaceutical optimization through a prodrug strategy afforded BMS-159, which markedly improved solubility and enabled oral delivery of the parent with acceptable bioavailability and pharmacokinetic properties suitable for further development.
Source: ACS Medicinal Chemistry Letters
Authors: Christine M. Tarby, Amy Hart, Honghe Wan, Liqi He, John Tokarski, Brian Fink, Yufen Zhao, Tram Huynh, Ashvinikumar Gavai, Kurt Zimmermann, Gregory Vite, Dolatrai Vyas, Jennifer Inghrim, Mary Obermeier, Aberra Fura, Paul Elzinga, John Hunt, Urvashi Roongta, Benjamin Henley, Jonathan Lippy, Arvind Mathur, Dauh Rurng Wu, Peng Li, Nirmala Raghavan, Gerry Everlof, Brent Rupnow, Francis Lee, Joseph Fargnoli, Jeffrey Tredup, Susan E. Kiefer, Deepa Calambur, Anuradha Gupta, Muthalagu Vetrichelvan, Murugaiah A. M. Subbaiah, Ashok V. Purandare
Institution: Bristol-Myers Squibb (United States)
Language: English
Subfield: Organic Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: green
OpenAlex ID: W7155218644