prodrug PARP inhibitor TSL-1502

An orally bioavailable glucuronide prodrug of TSL-1502M, an inhibitor of the nuclear enzyme poly(ADP-ribose) polymerase (PARP), with potential chemo/radiosensitizing and antineoplastic activities. Upon oral administration, prodrug PARP inhibitor TSL-1502 is selectively converted by the enzyme beta-glucuronidase in the tumor microenvironment (TME) to its active form TSL-1502M. TSL-1502M selectively targets and binds to PARP and prevents PARP-mediated DNA repair of DNA breaks via the base-excision repair pathway. This enhances the accumulation of DNA strand breaks and promotes genomic instability and eventually leads to G2/M arrest and apoptosis. This may enhance the cytotoxicity of DNA-damaging agents. PARP catalyzes post-translational ADP-ribosylation of nuclear proteins that signal and recruit other proteins to repair damaged DNA and is activated by DNA breaks. The PARP-mediated repair pathway is dysregulated in a variety of cancer cell types. Beta-glucuronidase accumulates in the TME upon release from necrotic tumor cells and certain inflammatory cells.