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

Wang H 1 , Chen M 2 , Sang X 3 , You X 3 , Wang Y 3 , Paterson IC 4 Show all authors , Hong W 5 , Yang X 6

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
Eur J Med Chem, 2020 Apr 01;191:112154.
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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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