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

Abstract

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 <i>N</i>-substituted piperazinone moiety were achieved. In particular, <b>Cpd36</b> was identified as a distinct PARP inhibitor, showing remarkable enzymatic activity not only toward PARP-1 (IC₅₀ = 0.94 nM) and PARP-2 (IC₅₀ = 0.87 nM) but also toward PARP-7 (IC₅₀ = 0.21 nM), as well as high selectivity over other PARP isoforms. Furthermore, <b>Cpd36</b> was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of <b>Cpd36</b> 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.