Synthesis and evaluation of novel N,N -dialkylcinnamic acid-based mitochondrial pyruvate carrier inhibitors: Biosynthetic and energetic lethality of targeting metabolic plasticity in cancer

ABSTRACT Novel functionalized cyanocinnamic acid based MPC inhibitors based on pharmacologically privileged N -piperazinyl and N- piperidinyl drug templates have been synthesized for potential cancer treatment. In vitro cell proliferation inhibition studies with these derivatives 2-4 show activity in the low micromolar range. Seahorse XFe96 based mitochondrial stress tests also illustrate the ability of 2-4 to potently and acutely inhibit numerous parameters of mitochondrial respiration in MDA-MB-231, WiDr, and 4T1 cells. Further analyses of the lead compound 3 in permeabilized 4T1 cells provide evidence of specific inhibition of pyruvate driven respiration without affecting glutamate or succinate fueled respiratory processes. Combination studies with GLUT1 inhibitor BAY-876 illustrate the capacity of compound 3 to inhibit metabolic plasticity in triple negative breast cancer MDA-MB-231 cells and is synergistic in inhibiting cell proliferation in aggressive stage IV breast cancer 4T1.