Poly(ADP-ribose) polymerases 1 (PARP1) is the most abundant and well characterized protein of PARP family members, catalyzing the polymerization of poly(ADP-ribose) on target proteins. PARP1 participates in a variety of cellular functions, including chromosome stability, signal transduction and the regulation of gene transcription. Inhibiting PARP1 prevents the repair of damaged DNA, leading to cell death. Small molecule PARP1 inhibitors have showed anti-tumor activity not only in combination with standard chemotherapy, but also in single therapy  in the treatment of tumors with DNA repair defect such as breast tumors with BRCA1/2 mutations.We identified a series of quinazolinedione derivatives as potent PARP1 inhibitors. Our lead compounds have potent in vitro activities, good DMPK profiles and significant in vivo efficacy in SW620 xenograft model. In this presentation, we will discuss synthetic method, the structure activity relationship (SAR) and pharmacological data of this series.

Discovery of quinazolinedione derivatives as potent PARP1 inhibitors

248th National Meeting (2014)

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