Abstract
Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cisenone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.
Keywords: Resorcylic acid lactones (RALs), irreversible protein kinase, MAPK kinases
Current Pharmaceutical Design
Title: Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors
Volume: 18 Issue: 9
Author(s): Linyi Wei, Jiuhong Wu, Guanqun Li and Ning Shi
Affiliation:
Keywords: Resorcylic acid lactones (RALs), irreversible protein kinase, MAPK kinases
Abstract: Resorcylic acid lactones (RALs) constitute a group of polyketide natural products with a large macrocyclic ring fused to resorcylic acid. Despite distinct core scaffold from all marketed kinase inhibitors, RALs bearing a cis-enone moiety have recently shown irreversible yet selective inhibition on a subset of kinases along the MAPK signaling pathway such as MEK, ERK and TAK1. The biochemical and structural studies have demonstrated that the cis-enone RALs can inhibit kinase activity by forming a covalent Michael adduct with an adequately positioned cysteine residue in the ATP binding pocket. This review discusses the mechanism of action, synthetic strategies, and structure-activity relationships (SARs) of cis-enone RALs. It is anticipated that design, synthesis and evaluation of cisenone RALs analogs will diversify the chemical space of kinase inhibitors and facilitate the development of new leads for the treatment of various diseases such as cancer and inflammatory disorders.
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Cite this article as:
Wei Linyi, Wu Jiuhong, Li Guanqun and Shi Ning, Cis-enone Resorcylic Acid Lactones (RALs) as Irreversible Protein Kinase Inhibitors, Current Pharmaceutical Design 2012; 18 (9) . https://dx.doi.org/10.2174/138161212799436395
DOI https://dx.doi.org/10.2174/138161212799436395 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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