Cell active and functionally-relevant small-molecule agonists of calcitonin receptor

Shuai Zhao; Shengchao Guo; Chan Yang; Zheng Gong; Yaomin Wang; Yingli Jia; Xinyu Jiang; Liwei Xu; Li Shi; Xiao Yu; Jinpeng Sun; Yan Zhang; Xin Chen

doi:10.1016/j.bioorg.2020.103596

Cell active and functionally-relevant small-molecule agonists of calcitonin receptor

Bioorg Chem. 2020 Mar:96:103596. doi: 10.1016/j.bioorg.2020.103596. Epub 2020 Jan 21.

Authors

Shuai Zhao¹, Shengchao Guo², Chan Yang³, Zheng Gong², Yaomin Wang¹, Yingli Jia³, Xinyu Jiang¹, Liwei Xu⁴, Li Shi⁴, Xiao Yu⁵, Jinpeng Sun⁶, Yan Zhang⁷, Xin Chen⁸

Affiliations

¹ Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu 213164, China.
² Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
³ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China.
⁴ Department of Tumor Hematology, The First Affiliated Hospital of Changchun University of Chinese Medicine, Changchun, Jilin 130021, China.
⁵ Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, Shandong University School of Medicine, Shandong 250012, China; Department of Physiology, Shandong University School of Medicine, Jinan, Shandong 250012, China.
⁶ Key Laboratory Experimental Teratology of the Ministry of Education and Department of Biochemistry and Molecular Biology, Shandong University School of Medicine, Jinan, Shandong 250012, China; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing 100191, China. Electronic address: sunjinpeng@sdu.edu.cn.
⁷ Department of Pathology of Sir Run Run Shaw Hospital and Department of Biophysics, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China. Electronic address: zhang_yan@zju.edu.cn.
⁸ Department of Medicinal Chemistry, School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu 213164, China. Electronic address: xinchen@cczu.edu.cn.

PMID: 32004895
DOI: 10.1016/j.bioorg.2020.103596

Abstract

The natural calcitonin (CT) receptor and its peptide agonists are considered validated targets for drug discovery. A small molecule agonist, SUN-B8155, has previously been shown to efficiently activate cellular CTR. Herein, we report the synthesis of a series of compounds (S8155 1-9) derived from SUN-B8155, and investigate the structural-functional relationship, bias properties and their cellular activity profile. We discover that the N-hydroxyl group from the pyridone ring is required for G protein activity and its affinity to the CT receptor. Among the compounds studied, S8155-7 exhibits improved G protein activity while S8155-4 displays a significant β-arrestin-2 signaling bias. Finally, we show that both S8155-4 and S8155-7 inhibit tumour cell invasion through CTR activation. These two compounds are anticipated to find extensive applications in chemical biology research as well drug development efforts targeting CT receptor.

Keywords: Agonist; Bias; CTR; GPCR; Migration.

Publication types

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

MeSH terms

HEK293 Cells
Humans
MCF-7 Cells
Pyridones / chemistry
Pyridones / pharmacology
Receptors, Calcitonin / agonists*
Receptors, Calcitonin / metabolism
Signal Transduction / drug effects
Small Molecule Libraries / chemistry*
Small Molecule Libraries / pharmacology*
beta-Arrestins / metabolism

Substances

Pyridones
Receptors, Calcitonin
Small Molecule Libraries
beta-Arrestins