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

Q1 · MEDICINE

Article

Author: Deng, Jialing ; Du, Tingting ; Sheng, Li ; Zhou, Jie ; Wang, Xiaoyu ; Ji, Ming ; Li, Yan ; Yao, Haiping ; Chen, Xiaoguang ; Xu, Bailing

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 N-substituted piperazinone moiety were achieved. In particular, Cpd36 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, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model. The crystal structures of Cpd36 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.

Journal of Medicinal Chemistry

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

Author: Sheng, Li ; Chen, Xiaoguang ; Deng, Jialing ; Ji, Ming ; Zhou, Jie ; Wang, Xiaoyu ; Du, Tingting ; Yao, Haiping ; Li, Yan ; Xu, Bailing

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 pharmacol. file still need enormous explorations.Herein, a series of novel highly potent PARP-1/2 inhibitors bearing an N-substituted piperazinone moiety were achieved.In particular, Cpd36 was identified as a distinct PARP inhibitor, showing remarkable enzymic 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, Cpd36 was orally bioavailable and significantly repressed the tumor growth in both breast cancer and prostate cancer xenograft model.The crystal structures of Cpd36 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.

International Journal of Molecular SciencesQ2 · BIOLOGY

A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2 Translocase

Q2 · BIOLOGY

ArticleOA

Author: Yu, Sung-Liang ; Chen, Yi-Ru ; Huang, Yi-Wei ; Chiu, Hao-Chieh ; Yang, Ching-Yi ; Zhang, Yao-Qing ; Tzeng, Shiou-Ru ; Chen, Ching S. ; Chien, Han-Sheng

The treatment of Staphylococcus aureus infections is impeded by the prevalence of MRSA and the formation of persisters and biofilms. Previously, we identified two celecoxib derivatives, Cpd36 and Cpd46, to eradicate MRSA and other staphylococci. Through whole-genome resequencing, we obtained several lines of evidence that these compounds might act by targeting the membrane protein translocase YidC2. Our data showed that ectopic expression of YidC2 in S. aureus decreased the bacterial susceptibility to Cpd36 and Cpd46, and that the YidC2-mediated tolerance to environmental stresses was suppressed by both compounds. Moreover, the membrane translocation of ATP synthase subunit c, a substrate of YidC2, was blocked by Cpd46, leading to a reduction in bacterial ATP production. Furthermore, we found that the thermal stability of bacterial YidC2 was enhanced, and introducing point mutations into the substrate-interacting cavity of YidC2 had a dramatic effect on Cpd36 binding via surface plasmon resonance assays. Finally, we demonstrated that these YidC2 inhibitors could effectively eradicate MRSA persisters and biofilms. Our findings highlight the potential of impeding YidC2-mediated translocation of membrane proteins as a new strategy for the treatment of bacterial infections.

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Indication	Highest Phase	Country/Location	Organization	Date
Breast Cancer	Preclinical	China	Institute of Materia Medica	16 Oct 2023
Prostatic Cancer	Preclinical	China	Institute of Materia Medica	16 Oct 2023

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