作为致癌蛋白激酶抑制剂的肉桂酸衍生物的结构、机制和生物效应#

Title:Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases – Structure, Mechanisms and Biomedical Effects#

Volume: 23 Issue: 10

Author(s): Marcin Mielecki, Bogdan Lesyng

Affiliation:

关键词: 抗肿瘤，融合蛋白，肉桂酸，酯姜黄素，CK2，姜黄素，表皮生长因子受体，人类表皮生长因子受体II，JAK2，激酶，雷帕霉素靶蛋白信号传导与转录激活子，PIM1

摘要: Cinnamic acid belongs to phenolic-acid class of polyphenols, one of the most abundant plant secondary metabolites. These substances are widely studied because of plethora of their biological activities. In particular, their inhibition of protein kinases contributes to the pleiotropic effects in the cell. Protein kinases are essential in controlling cell signaling networks. Selective targeting of oncogenic protein kinases increases clinical anticancer efficacy. Cinnamic acid and related compounds have inspired researchers in the design of numerous synthetic and semisynthetic inhibitors of oncogenic protein kinases for the past three decades. Interest in cinnamoyl-scaffold-containing compounds revived in recent years, which was stimulated by modern drug design and discovery methodologies such as in vitro and in silico HTS. This review presents cinnamic acid derivatives and analogs for which direct inhibition of protein kinases was identified. We also summarize significance of the above protein kinase families – validated or promising targets for anticancer therapies. The inhibition mode may vary from ATP-competitive, through bisubstrate-competitive and mixedcompetitive, to non-competitive one. Kinase selectivity is often correlated with subtle chemical modifications, and may also be steered by an additional non-cinnamoyl fragment of the inhibitor. Specific cinnamic acid congeners may synergize their effects in the cell by a wider range of activities, like suppression of additional enzymes, e.g. deubiquitinases, influencing the same signaling pathways (e.g. JAK2/STAT). Cinnamic acid, due to its biological and physicochemical properties, provides nature-inspired ideas leading to novel inhibitors of oncogenic protein kinases and related enzymes, capable to target a variety of cancer cells.

Cite this article as:

Marcin Mielecki, Bogdan Lesyng , Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases – Structure, Mechanisms and Biomedical Effects#, Current Medicinal Chemistry 2016; 23 (10) . https://dx.doi.org/10.2174/0929867323666160316123609