Title:Cinnamic Acid Derivatives as Inhibitors of Oncogenic Protein Kinases – Structure, Mechanisms and Biomedical Effects#
Volume: 23
Issue: 10
Author(s): Marcin Mielecki and Bogdan Lesyng
Affiliation:
Keywords:
Anticancer, BCR-ABL, cinnamic acid, CK2, curcumin, EGFR, HER2, JAK2, kinase, mTOR, PIM1,
PIM2, RIO1, RSK2, STAT, tyrphostin.
Abstract: 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.
