Development of small molecule inhibitors targeting TGF-β ligand and receptor: Structures, mechanism, preclinical studies and clinical usage

Hao Wang; Meiling Chen; Xiaohong Sang; Xuefu You; Yucheng Wang; Ian C Paterson; Wei Hong; Xinyi Yang

doi:10.1016/j.ejmech.2020.112154

Development of small molecule inhibitors targeting TGF-β ligand and receptor: Structures, mechanism, preclinical studies and clinical usage

Eur J Med Chem. 2020 Apr 1:191:112154. doi: 10.1016/j.ejmech.2020.112154. Epub 2020 Feb 18.

Authors

Hao Wang¹, Meiling Chen², Xiaohong Sang³, Xuefu You³, Yucheng Wang³, Ian C Paterson⁴, Wei Hong⁵, Xinyi Yang⁶

Affiliations

¹ School of Pharmacy, Minzu University of China, Beijing, 100081, China; Key Laboratory of Ethnomedicine (Minzu University of China), Ministry of Education, Beijing, 100081, China.
² School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan, 750021, China; Key Laboratory of Chemical Engineering and Technology, State Ethnic Affairs Commission, North Minzu University, Yinchuan, 750021, China.
³ Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China.
⁴ Department of Oral and Craniofacial Sciences and Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
⁵ School of Chemistry and Chemical Engineering, North Minzu University, Yinchuan, 750021, China; Key Laboratory of Chemical Engineering and Technology, State Ethnic Affairs Commission, North Minzu University, Yinchuan, 750021, China. Electronic address: hongwei@nmu.edu.cn.
⁶ Laboratory of Pharmacology/Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address: xinyiyang@imb.cams.cn.

PMID: 32092587
DOI: 10.1016/j.ejmech.2020.112154

Abstract

Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and differentiation. Following binding to type I and II TGF-β serine/threonine kinase receptors, TGF-β activates downstream signaling cascades involving both SMAD-dependent and -independent pathways. Aberrant TGF-β signaling is associated with a variety of diseases, such as fibrosis, cardiovascular disease and cancer. Hence, the TGF-β signaling pathway is recognized as a potential drug target. Various organic molecules have been designed and developed as TGF-β signaling pathway inhibitors and they function by either down-regulating the expression of TGF-β or by inhibiting the kinase activities of the TGF-β receptors. In this review, we discuss the current status of research regarding organic molecules as TGF-β inhibitors, focusing on the biological functions and the binding poses of compounds that are in the market or in the clinical or pre-clinical phases of development.

Keywords: SMAD signaling pathway; Small-molecule inhibitor; TGF-β; TGF-β receptor.

Publication types

Review

MeSH terms

Animals
Drug Development*
Humans
Ligands
Molecular Structure
Pyrazoles / chemical synthesis
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Receptors, Transforming Growth Factor beta / metabolism
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*
Transforming Growth Factor beta / antagonists & inhibitors*
Transforming Growth Factor beta / metabolism

Substances

Ligands
Pyrazoles
Receptors, Transforming Growth Factor beta
Small Molecule Libraries
Transforming Growth Factor beta
pyrazole