Design, synthesis and biological evaluation of novel pyrrolo[1,2-b]pyridazin-2(1H)-ones as selective PARP1 inhibitors for cancer therapy.

Poly-ADP-ribose-polymerase inhibitors (PARPi) hold significant clinical value in the treatment of BRCA-deficient tumors, but their substantial hematological toxicity limits a broader scope of clinical applications. Studies suggest that the toxicity may be associated with selective deficiency between PARP1 and PARP2. In this study, we designed and synthesized a series of inhibitors containing novel pyrrolo[1,2-b]pyridazin-2(1H)-one scaffold selectively targeting PARP1. Among these compounds, YCH3971 exhibited potent inhibiting activity against PARP1 with an IC50 of 7.52 nM, showing a remarkable subtype selectivity compared with PARP2 (>1000-fold). Also, YCH3971 possessed a strong antiproliferative activity on BRCA mutant MDA-MB-436 cells with an IC50 of 2.10 nM. However, since the oral bioavailability of YCH3971 in rats is only 1.2%, we have not yet initiated in vivo efficacy studies.