Discovery of Pyrazolo[1,5,4-de]quinoxalin-2(3<i>H</i>)‑one Derivatives as Highly Potent and Selective\nPARP1 Inhibitors

Poly-ADP-ribose-polymerase\n1/2 (PARP1/2) inhibitors have been approved\nfor cancers with homologous recombination deficiency (HRD). However,\ntheir narrow therapeutic indexes largely due to hematologic toxicities\nhave limited their clinical usefulness. Developing selective PARP1\ninhibitors has emerged as an attractive strategy to achieve equivalent\nantitumor activity while alleviating the hematological toxicity caused\nby 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\nto better potency in inhibiting cancer cell proliferation. <b>30</b> achieved tumor regression in the BRCA1-mutated MDA-MB-436 xenograft\nmodel and showed synergistic efficacy in combination with carboplatin\nin the SUM149PT xenograft model. In the rat hematological toxicity\nstudy, <b>30</b> exhibited minimal impact on hematological parameters\nat 25 mg/kg, while AZD5305 at 1 mg/kg caused 56.5% reduction of reticulocyte.\nTaken together, we discovered compound <b>30</b> with a therapeutic\nindex superior to that of PARP1 inhibitors AZD5305 and AZD9574 in\nthe preclinical setting.