Premium
Unnatural Polyketide Analogues Selectively Target the HER Signaling Pathway in Human Breast Cancer Cells
Author(s) -
Kwon Seok Joon,
Kim Moon Il,
Ku Bosung,
Coulombel Lydie,
Kim JinHwan,
Shawky Joseph H.,
Linhardt Robert J.,
Dordick Jonathan S.
Publication year - 2010
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200900674
Subject(s) - polyketide , curcumin , receptor tyrosine kinase , chalcone , chemistry , biochemistry , lapatinib , chalcone synthase , polyketide synthase , kinase , tyrosine kinase , biology , signal transduction , cancer research , cancer , stereochemistry , breast cancer , enzyme , biosynthesis , genetics , trastuzumab
Receptor tyrosine kinases are critical targets for the regulation of cell survival. Cancer patients with abnormal receptor tyrosine kinases (RTK) tend to have more aggressive disease with poor clinical outcomes. As a result, human epidermal growth factor receptor kinases, such as EGFR (HER1), HER2, and HER3, represent important therapeutic targets. Several plant polyphenols including the type III polyketide synthase products (genistein, curcumin, resveratrol, and epigallocatechin‐3‐galate) possess chemopreventive activity, primarily as a result of RTK inhibition. However, only a small fraction of the polyphenolic structural universe has been evaluated. Along these lines, we have developed an in vitro route to the synthesis and subsequent screening of unnatural polyketide analogues with N‐acetylcysteamine (SNAc) starter substrates and malonyl‐coenzyme A (CoA) and methylmalonyl‐CoA as extender substrates. The resulting polyketide analogues possessed a similar structural polyketide backbone (aromatic‐2‐pyrone) with variable side chains. Screening chalcone synthase (CHS) reaction products against BT‐474 cells resulted in identification of several trifluoromethylcinnamoyl‐based polyketides that showed strong suppression of the HER2‐associated PI3K/AKT signaling pathway, yet did not inhibit the growth of nontransformed MCF‐10A breast cells (IC 50 >100 μ M ). Specifically, 4‐trifluoromethylcinnamoyl pyrone (compound 2 e ) was highly potent (IC 50 <200 n M ) among the test compounds toward proliferation of several breast cancer cell lines. This breadth of activity likely stems from the ability of compound 2 e to inhibit the phosphorylation of HER1, HER2, and HER3. Therefore, these polyketide analogues might prove to be useful drug candidates for potential breast cancer therapy.