4.7 Article

Recent advances in development of hetero-bivalent kinase inhibitors

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出版社

ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2021.113318

关键词

Hetero-bivalent; Protein kinase; Kinase inhibitor; Type V inhibitor

资金

  1. Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [NRF-2018R1D1A1B07045101]
  2. Bio & Medical Technology Development Program of the National Research Foundation (NRF) - Korean government (MSIT) [NRF-2017M3A9G7072568]

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Bivalent kinase inhibitors have emerged as a promising approach for targeting specific kinases with enhanced selectivity and affinity through increased interactions with target enzymes. Recent developments have led to the creation of bivalent compounds with high kinase affinity, biological and chemical stability in vivo, offering significant potential for therapeutic applications. This review provides a comprehensive overview of hetero-bivalent kinase inhibitors and discusses their advantages, limitations, and future prospects compared to monovalent kinase inhibitors.
Identifying a pharmacological agent that targets only one of more than 500 kinases present in humans is an important challenge. One potential solution to this problem is the development of bivalent kinase inhibitors, which consist of two connected fragments, each bind to a dissimilar binding site of the bisubstrate enzyme. The main advantage of bivalent (type V) kinase inhibitors is generating more interactions with target enzymes that can enhance the molecules' selectivity and affinity compared to single-site inhibitors. Earlier type V inhibitors were not suitable for the cellular environment and were mostly used in in vitro studies. However, recently developed bivalent compounds have high kinase affinity, high biological and chemical stability in vivo. This review summarized the hetero-bivalent kinase inhibitors described in the literature from 2014 to the present. We attempted to classify the molecules by serine/threonine and tyrosine kinase inhibitors, and then each target kinase and its hetero-bivalent inhibitor was assessed in depth. In addition, we discussed the analysis of advantages, limitations, and perspectives of bivalent kinase inhibitors compared with the monovalent kinase inhibitors. (C) 2021 Elsevier Masson SAS. All rights reserved.

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