Jonnalagadda Shirisha, Jonnalagadda Sravan K, Ronayne Conor T, Nelson Grady L, Solano Lucas N, Rumbley Jon, Holy Jon, Mereddy Venkatram R, Drewes Lester R
Integrated Biosciences Graduate Program, University of Minnesota, Duluth, MN 55812, USA.
Department of Pharmacy Practice & Pharmaceutical Sciences, University of Minnesota, Duluth, MN 55812, USA.
Oncotarget. 2019 Mar 22;10(24):2355-2368. doi: 10.18632/oncotarget.26760.
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 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. 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. 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.
基于α-氰基肉桂酸结构模板，首次开发出强效双特异性单羧酸转运蛋白（MCT）1和4抑制剂作为潜在的抗癌药物。已对候选抑制剂1-9针对表达MCT1和MCT4的癌细胞系进行细胞增殖评估。通过同源建模和分子对接预测研究了先导化合物9与MCT1和MCT4的潜在结合相互作用。通过糖酵解对细胞外通量的影响和线粒体应激测试表明，候选化合物3和9在表达MCT1的结肠腺癌WiDr细胞和表达MCT4的三阴性乳腺癌MDA-MB-231细胞中能有效破坏糖酵解和氧化磷酸化。这些细胞中的荧光显微镜分析还表明化合物9被内化并聚集在线粒体附近。在小鼠的WiDr和MDA-MB-231异种移植肿瘤模型中进行的肿瘤生长抑制研究表明，候选化合物9具有显著的单药活性。
