Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on a-cyanocinnamic acid structural template. Candidate inhibitors 1-9 have been evaluated for in vitro cell proliferation against MCT1 and MCT4 expressing cancer cell lines. Potential MCT1 and MCT4 binding interactions of the lead compound 9 have been studied through homology modeling and molecular docking prediction. In vitro effects on extracellular flux via glycolysis and mitochondrial stress tests suggest that candidate compounds 3 and 9 disrupt glycolysis and OxPhos efficiently in MCT1 expressing colorectal adenocarcinoma WiDr and MCT4 expressing triple negative breast cancer MDA-MB-231 cells. Fluorescence microscopy analyses in these cells also indicate that compound 9 is internalized and concentrated near mitochondria. In vivo tumor growth inhibition studies in WiDr and MDA-MB-231 xenograft tumor models in mice indicate that the candidate compound 9 exhibits a significant single agent activity.
Bibliographical noteFunding Information:
This work was supported by University of Minnesota Duluth; Department of Defense Breast Cancer Research Proposal, Breakthrough Award (grant number W81XWH-15-1-0047, VRM); Department of Defense Breast Cancer Research Award (grant number W81XWH-15-1-0060, LRD), Whiteside Clinical Research Institute, Duluth, Minnesota.
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- 2-alkoxy-N,N-dialkyl cyanocinnamic acid
- Monocarboxylate transporter 1 inhibitor
- Monocarboxylate transporter 4 inhibitor