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

// Shirisha Jonnalagadda 1 , Sravan K. Jonnalagadda 1 , Conor T. Ronayne 1 , Grady L. Nelson 1 , Lucas N. Solano 1 , Jon Rumbley 1, 2 , Jon Holy 1, 3 , Venkatram R. Mereddy 1, 2, 4 and Lester R. Drewes 1, 3 1 Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA 2 Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA 3 Department of Biomedical Sciences, Medical School Duluth, University of Minnesota, Duluth, MN 55812, USA 4 Department of Chemistry and Biochemistry, University of Minnesota, Duluth, MN 55812, USA Correspondence to: Lester R. Drewes, email: ldrewes@d.umn.edu Venkatram R. Mereddy, email: vmereddy@d.umn.edu Keywords: monocarboxylate transporter 1 inhibitor; monocarboxylate transporter 4 inhibitor; 2-alkoxy- N,N -dialkyl cyanocinnamic acid; cancer; metabolism Received: December 02, 2018      Accepted: February 22, 2019      Published: March 22, 2019 ABSTRACT Potent and dual monocarboxylate transporter (MCT) 1 and 4 inhibitors have been developed for the first time as potential anticancer agents based on α-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.