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

Journal of Medicinal Chemistry, Год журнала: 2024, Номер unknown

Опубликована: Ноя. 21, 2024

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 limited clinical usefulness. Developing selective PARP1 has emerged as an attractive strategy achieve equivalent antitumor activity while alleviating the hematological toxicity caused by PARP2 inhibition. Herein, we report discovery of pyrazolo[1,5,4-de]quinoxalin-2(3H)-one 30 a novel inhibitor. formed tighter PARP1-DNA trapping than AZD9574, leading better potency in inhibiting cancer cell proliferation. achieved tumor regression BRCA1-mutated MDA-MB-436 xenograft model and showed synergistic efficacy combination carboplatin SUM149PT model. In rat study, exhibited minimal impact on parameters at 25 mg/kg, AZD5305 1 mg/kg 56.5% reduction reticulocyte. Taken together, discovered compound index superior that AZD9574 preclinical setting.

Язык: Английский

Advancements of anticancer agents by targeting the Hippo signalling pathway: biological activity, selectivity, docking analysis, and structure–activity relationship

Molecular Diversity, Год журнала: 2024, Номер unknown

Опубликована: Окт. 22, 2024

Язык: Английский