SAR study of 1,2-benzisothiazole dioxide compounds that agonize HIF-2 stabilization and EPO production

Wanbin Song; Jingjing Zhuang; Nan Zhang; Xintong Ren; Weiwei Xu; Mengqi Guo; Xiaotong Diao; Chao Liu; Jiaming Jin; Dalei Wu; Yinan Zhang

doi:10.1016/j.bmc.2022.117041

SAR study of 1,2-benzisothiazole dioxide compounds that agonize HIF-2 stabilization and EPO production

Bioorg Med Chem. 2023 Jan 1:77:117041. doi: 10.1016/j.bmc.2022.117041. Epub 2022 Oct 3.

Authors

Wanbin Song¹, Jingjing Zhuang², Nan Zhang¹, Xintong Ren³, Weiwei Xu¹, Mengqi Guo³, Xiaotong Diao³, Chao Liu³, Jiaming Jin¹, Dalei Wu⁴, Yinan Zhang⁵

Affiliations

¹ Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
² Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China; Marine College, Shandong University, Weihai 264209, China.
³ Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.
⁴ Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China. Electronic address: [email protected].
⁵ Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China. Electronic address: [email protected].

PMID: 36521398
DOI: 10.1016/j.bmc.2022.117041

Abstract

Benzisothiazole dioxide compound was reported to agonize HIF-2 stabilization and improve EPO production, thus conceiving a potential strategy to treat disease with chronic hypoxia exemplified by renal anemia. Herein, on the bases of multiple molecular and cellular assays, a series of benzisothiazole derivatives have been synthesized and their structure-activity relationship was evaluated. The SAR and molecular docking studies have revealed the structural insights on the rational design of HIF-2 agonist and discovered a more potential 5-bromine substituted analogue, which showed 2-4 times improvement of HIF-2 downstream gene transcriptions, including EPO production. The present results suggest the therapeutic potential of the compounds for diseases related to EPO insufficiency.

Keywords: Agonist; Benzisothiazole; EPO; HIF-2; SAR.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anemia* / drug therapy
Basic Helix-Loop-Helix Transcription Factors
Erythropoietin* / genetics
Erythropoietin* / pharmacology
Humans
Molecular Docking Simulation

Substances

Erythropoietin
benzisothiazole
Basic Helix-Loop-Helix Transcription Factors