Discovery of Quinazoline-2,4(1,3)-dione Derivatives Containing a Piperizinone Moiety as Potent PARP-1/2 Inhibitors─Design, Synthesis, Antitumor Activity, and X-ray Crystal Structure Analysis.

PARP-1/2 inhibitors have become an important therapeutic strategy for the treatment of HR-deficient tumors. However, discovery of new inhibitors with an improved and distinct pharmacological file still need enormous explorations. Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an -substituted piperazinone moiety were achieved. In particular, was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC = 0.94 nM) and PARP-2 (IC = 0.87 nM) but also toward PARP-7 (IC = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of within PARP-1 and PARP-2 together with the predicted binding mode within PARP-7 revealed its binding features and provided insightful information for further developing highly potent and selective PARP-1 and/or PARP-7 inhibitors.