Definition

An intratumoral (IT) formulation of a derivative of 3-bromopyruvate (3-BP), with potential antineoplastic activity. Upon IT administration of 3-BP-based agent KAT-201, the 3-BP derivative, being structurally similar to lactic acid, specifically binds to and enters cancer cells through monocarboxylic acid transporters (MCTs), which are transporters for lactic acid and are overexpressed on cancer cells. Inside the cancer cells, KAT-201 interferes with both glycolysis and mitochondrial oxidative phosphorylation (OxPhos), thereby depleting adenosine triphosphate (ATP) levels and thus limits energy supply needed by cancer cells to proliferate. This induces cancer cell apoptosis and prevents cancer cell proliferation. In addition, KAT-201 is able to release mitochondrial-bound hexokinase (HK) II (HK2) from the mitochondria, thereby allowing mitochondrial voltage-dependent anion channels (VDACs) to bind to pro-apoptotic proteins and increases the formation of mitochondrial permeability transition pores (MPTPs), which induces apoptosis. KAT-201 also inhibits a variety of enzymes, including lactate dehydrogenase (LDH), pyruvate dehydrogenase (PDH) and pyruvate dehydrogenase kinase (PDHK). This further prevents cancer cells’ metabolism. HK2 is overexpressed in cancer cells and plays a major role in glycolysis and preventing tumor cell apoptosis. It is bound to VDAC in cancer cells and prevents VDAC’s interaction with pro-apoptotic proteins which prevents apoptosis.