Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N-methylpyridine-2-carboxamide (AZD5305): A PARP1-DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs
Poly-ADP-ribose polymerase (PARP) inhibitors have received regulatory approval for the treatment of tumors with homologous recombination repair deficiencies, including those with BRCA mutations. However, some PARP inhibitors have failed in combination with first-line chemotherapies, primarily due to overlapping hematological toxicities. A key limitation of currently approved PARP inhibitors is their lack of selectivity for PARP1 over PARP2 and other members of the PARP family, which may contribute to these toxicities. Recent studies have highlighted that PARP1 inhibition and PARP1-DNA trapping are essential for therapeutic efficacy in tumors with BRCA mutations.
In this study, we describe the design and development of compound 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1-DNA trapper that shows strong in vivo efficacy in a BRCA mutant HBCx-17 patient-derived xenograft (PDX) model. AZD5305 exhibits high selectivity for PARP1 over other PARP family members, with favorable secondary pharmacology, physicochemical properties, and excellent pharmacokinetics in preclinical species. Additionally, it demonstrates reduced toxicity on human bone marrow progenitor cells in vitro, suggesting a potentially improved safety profile compared to other PARP inhibitors.