Juan Xu: College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
Anmin Zhao: College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China.
Danni Chen: College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China.
Jiao Wang: College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China.
Jirui Ma: College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China.
Luolong Qing: Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China.
Yuanyuan Li: School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
Huan He: Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China. Electronic address: ivy@whu.edu.cn.
Weidong Pan: Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China. Electronic address: wdpan@163.com.
Silong Zhang: Key Laboratory of Plant Resource Conservation and Germplasm Innovation in Mountainous Region (Ministry of Education), School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China. Electronic address: silongzhang@whu.edu.cn.
PARP7 has been recently identified as an effective drug target due to its specific role in tumor generation and immune function recovery. Herin, we report the discovery of compound 8, which contained a tricyclic fused ring, as a highly selective PARP7 inhibitor against other PARPs. In particular, compound 8 strongly inhibits PARP7 with an IC of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung cancer cells with an IC of 2.5 nM. Compound 8 exhibits a favorable pharmacokinetic profile with a bioavailability of 104 % in mice, and 78 % in dogs. Importantly, daily treatment of 30 mg/kg of 8 induced 81.6 % tumor suppression in NCI-H1373 lung xenograft mice tumor models, which is significantly better than the clinical candidate, RBN-2397. These intriguing features highlight the promising advantages of 8 as an antitumor agent.
