Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3<i>H</i>)-one Derivatives as Highly Potent and Selective PARP1 Inhibitors

Poly-ADP-ribose-polymerase 1/2 (PARP1/2) inhibitors have been approved for cancers with homologous recombination deficiency (HRD). However, their narrow therapeutic indexes largely due to hematologic toxicities have limited their clinical usefulness. Developing selective PARP1 inhibitors has emerged as an attractive strategy to achieve equivalent antitumor activity while alleviating the hematological toxicity caused by PARP2 inhibition. Herein, we report the discovery of pyrazolo[1,5,4-de]quinoxalin-2(3<i>H</i>)-one <b>30</b> as a novel selective PARP1 inhibitor. <b>30</b> formed tighter PARP1-DNA trapping than AZD9574, leading to better potency in inhibiting cancer cell proliferation. <b>30</b> achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy in combination with carboplatin in the SUM149PT xenograft model. In the rat hematological toxicity study, <b>30</b> exhibited minimal impact on hematological parameters at 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte. Taken together, we discovered compound <b>30</b> with a therapeutic index superior to that of PARP1 inhibitors AZD5305 and AZD9574 in the preclinical setting.