Synthesis of triazolopyrimidinone- and imidazotriazinone-based tankyrase inhibitors: Identification of Basroparib (STP1002) as a clinical candidate

We report the design, synthesis, and characterization of a novel series of triazolopyrimidinone and imidazotriazinone derivatives as potent and selective TNKS1/2 inhibitors. These compounds bind to the nicotinamide pocket of TNKS and exhibit strong enzymatic inhibition and cellular Wnt/β-catenin pathway suppression, with minimal off-target activity against other PARP family members. Among them, 11b (STP1002, Basroparib) demonstrated the most favorable profile, with sub-nanomolar IC₅₀ values for TNKS1/2, high selectivity, and excellent physicochemical and ADME properties. These findings support the further development of STP1002 as a promising therapeutic candidate for Wnt-driven cancers, with potential applications as both a monotherapy and in combination with other targeted agents.