Cellular transporters as novel metabolic immune checkpoints: NGY-091, a small molecule dual MCT1/4 inhibitor for immuno oncology

Background: Aberrant metabolic reprogramming of malignant cells is known to drive cancer progression and metastasis. The increase in glycolytic flux creates a lactate-rich tumor microenvironment (TME), which tumors exploit by expanding immunosuppressive cell populations such as Tregs MDSCs that thrive on lactate fuel source. Blockade export from cells, while inhibiting uptake suppressive immune novel therapeutic strategy treat cancer. Lactate transport predominantly mediated MCT1 MCT4 transporters. We have developed compound, NGY-091, first-in-class small molecule dual inhibitor the Materials Methods: direct cytotoxic effect NGY-091 was examined multiple lines. on-target activity validated measuring intracellular extracellular levels. vivo efficacy studied using CDX, PDX syngeneic models. Immune profiling performed 2 weeks after treating animals with flow cytometry. Results: treatment exhibited potent vitro cytotoxicity against various levels expressions. strongly blocked import through under high conditions glucose conditions. also inhibited pyruvate entry into mitochondria MPC1. Furthermore, killing evident human CDX models NGY-091. In 4T1 MC38 murine tumors, we observed significant growth inhibition treatment, strong synergistic reduction when combined checkpoint inhibitors. Profiling lymphoid myeloid treated cytometry revealed alteration architecture suggesting activation antitumor immunity. induced profound effector T populations, CD8/Treg ratio, tumor-suppressive M1 macrophages, significantly downregulating M2 macrophages. To further investigate if directly alters functionality vitro, CD4 T, CD8T, Tregs, culture condition, mimicked level TME. increased CD4+ CD8+ meanwhile it reduced function Treg vitro. Conclusions: These findings indicate validate observations tumors. Therefore, intervenes two key hallmarks cancer, metabolism immunity provides modality therapeutically target Conflict interest: Ownership: Nirogy Therapeutics