Design, Synthesis, and Pharmacodynamic Evaluation of Highly Selective PARP1 Inhibitors with Brain Penetrance

Selective poly(ADP-ribose) polymerase 1 (PARP1) inhibitors not only exhibit antitumor efficacy but also offer the potential to mitigate the toxicities typically associated with broader PARP inhibition. In this study, we designed and synthesized a series of small molecules targeting highly selective PARP1 inhibitors. Among these, T26 demonstrated excellent selectivity to PARP1 along with the capability to effectively cross the blood-brain barrier (BBB). T26 exhibited an IC₅₀ of 0.2 nM against PARP1, with a remarkable 610-fold selectivity over PARP2 and high antiproliferative activity in BRCA mutant MDA-MB-436 cells with an IC₅₀ of 2.6 nM. T26 also displayed excellent oral bioavailability (F = 87.74%) and long half-life (T_1/2 = 76.07 h) in mice, supporting once every other day administration. Oral administration of T26 at 0.3 mg/kg and 3 mg/kg resulted in significant tumor growth inhibition in both subcutaneous and intracranial xenograft models of MDA-MB-436, suggesting T26 significant potential for the treatment of breast cancer metastases.