Development of novel mitochondrial pyruvate carrier inhibitors for breast cancer treatment

Abstract

Reprogrammed metabolism of cancer cells offers a unique target for pharmacological intervention. The mitochondrial pyruvate (Pyr) carrier (MPC) plays important roles in cancer progression by transporting cytosolic Pyr into the mitochondria for use in the tricarboxylic acid cycle. In the current study, a series of novel fluoro-substituted aminocarboxycoumarin derivatives have been evaluated for their MPC inhibition properties. Our studies indicate that the aminocarboxycoumarin template elicits potent MPC inhibitory characteristics, and specifically, structure-activity relationship studies show that the N-methyl-N-benzyl structural template provides the optimal inhibitory capacity. Further respiratory experiments demonstrate that candidate compounds specifically inhibit Pyr-driven respiration without substantially affecting other metabolic fuels, consistent with MPC inhibition. Further, computational inhibitor docking studies illustrate that aminocarboxycoumarin-binding characteristics are nearly identical to that of classical MPC inhibitor UK5099 bound to human MPC, recently determined by cryo-EM. The lead candidate C5 elicits cancer cell proliferation inhibition specifically in monocarboxylate transporter 1-expressing murine breast cancer cells 4T1 and 67NR, consistent with its ability to accumulate intracellular lactate. In vivo tumor growth studies illustrate that C5 significantly reduces the tumor burden in two syngeneic murine tumor models with 4T1 and 67NR cells. These studies provide novel MPC inhibitors with potential for anticancer applications in monocarboxylate transporter 1-expressing breast cancer tumor models.

Keywords: aminocarboxycoumarin; breast cancer; medicinal chemistry; mitochondrial pyruvate carrier; tumor metabolism.