2. Academic Validation
  3. Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability

Discovery of tricyclic PARP7 inhibitors with high potency, selectivity, and oral bioavailability

  • Eur J Med Chem. 2024 Feb 15:266:116160. doi: 10.1016/j.ejmech.2024.116160.
Juan Xu 1,  Anmin Zhao 2,  Danni Chen 2,  Jiao Wang 2,  Jirui Ma 2,  Luolong Qing 3,  Yuanyuan Li 4,  Huaxiang Fang 5,  Huan He 6,  Weidong Pan 7,  Silong Zhang 8
Affiliations

Affiliations

  • 1 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.
  • 2 College of Chemistry and Chemical Engineering, Hubei Key Laboratory of Mine Environmental Pollution Control & Remediation, Hubei Polytechnic University, Huangshi, 435003, PR China.
  • 3 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.
  • 4 School of Life Science and Technology, Wuhan Polytechnic University, Wuhan, 430023, PR China; Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
  • 5 Wuhan Yuxiang Pharmaceutical Technology Co., Ltd., Wuhan, 430200, PR China.
  • 6 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.
  • 7 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.
  • 8 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.
PMID: 38277917 DOI: 10.1016/j.ejmech.2024.116160
Abstract

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 IC50 of 0.11 nM, and suppresses the proliferation of NCI-H1373 lung Cancer cells with an IC50 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.

Keywords

ADME-T; Cyclization; PARP7; Pharmacokinetic; Selectivity.

Figures
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z