Otto Warburg, in 1924, first observed that tumors utilize high amounts of glucose and produce lactic acid even in the presence of ample oxygen.
Nirogy Therapeutics is developing first-in-class medicines by targeting cell membrane-bound “solute carrier transporters” (SLCTs), which control the import and export of various molecules “in and out” of cells in our body. SLCT family of proteins is the largest family of transporters encoded by human genome and includes >450 proteins. SLCTs act as gatekeepers in essential physiological functions, including nutrient uptake, metabolite transport, waste disposal, etc. for maintaining homeostasis in the body. SLCTs are a largely underexplored source of new therapeutic targets; only less than 20 of >450 transporters are targeted by current drugs, leaving a huge trove of untapped drug targets, many of which are “orphan targets” – biological function and substrate specificity are unknown.
The dysregulation of cellular metabolism and metabolite transport lead to many pathological conditions. To unlock the therapeutic potential of SLCTs, Nirogy has focused initially on few transporter targets directed toward cancer, autoimmunity, and inflammation for which no known SLCT drugs exist.
Monocarboxylate Transporters (MCTs) are a subfamily of SLCTs consisting of 14 metabolite transporters. Of those, MCT1 and MCT4 are key isoforms that transport Lactate metabolite “in and out” of cells in a bidirectional fashion.
One-hundred years ago, Otto Warburg first observed that tumors utilize unusually high amounts of glucose (blood sugar) as the food source and produce lactic acid compared to normal cells in the body without using ample oxygen available for energy production – the phenomenon termed as the “Warburg effect”. This effect results from metabolic reprogramming during oncogenic transformation in cancer to generate the building blocks required for continuous cell proliferation and rapid growth relative to normal cells. Lactate metabolite is formed as a strong acid from glycolysis within the cell and is exported out of the cell through MCT1 and MCT4 to prevent its buildup inside the cell, which is detrimental to cancer cell survival. On the other hand, the exported lactate accumulates and acidifies the extracellular space in the tumor microenvironment (TME), creating a hostile environment for immune cells to survive and thereby making our body’s natural immune system unable to attack the tumor.
Nirogy has discovered a series of small molecule dual inhibitors that bind to both MCT1 and MCT4 (dMCTi), which can block lactate export, thus directly killing cancer cells and simultaneously restoring the immune function by lowering the acidity in the TME.
*Yong Zhang, et.al., “The SLC Transporter in nutrient and metabolic sensing, regulation, and drug development”, Journal of Molecular Cell Biology (2019), 11(1), 1-13.
*Brandon Faubert et.al., Cell (2017), 171, 358-371.