Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors

Shirisha Jonnalagadda, Sravan K. Jonnalagadda, Conor T. Ronayne, Grady L. Nelson, Lucas N. Solano, Jon N Rumbley, Jon M Holy, Venkatram R Mereddy, Lester R Drewes

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2355-2368
Number of pages14
JournalOncotarget
Volume10
Issue number24
DOIs
StatePublished - Mar 22 2019

Keywords

  • 2-alkoxy-N,N-dialkyl cyanocinnamic acid
  • Cancer
  • Metabolism
  • Monocarboxylate transporter 1 inhibitor
  • Monocarboxylate transporter 4 inhibitor

PubMed: MeSH publication types

  • Journal Article

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    Jonnalagadda, S., Jonnalagadda, S. K., Ronayne, C. T., Nelson, G. L., Solano, L. N., Rumbley, J. N., Holy, J. M., Mereddy, V. R., & Drewes, L. R. (2019). Novel N,N-dialkyl cyanocinnamic acids as monocarboxylate transporter 1 and 4 inhibitors. Oncotarget, 10(24), 2355-2368. https://doi.org/10.18632/oncotarget.26760