UCK2 Inhibitors

UCK2 inhibitors, as a chemical class, would be compounds that specifically target the enzymatic activity of Uridine-Cytidine Kinase 2. These inhibitors would bind to the active site of UCK2 or to its allosteric sites to prevent the conversion of uridine and cytidine to their respective monophosphates. Since UCK2 is important for the salvage pathway of pyrimidine nucleotides, its inhibition would primarily affect the cellular availability of UMP and CMP, which are essential for RNA and DNA synthesis. Although no specific UCK2 inhibitors have been reported, compounds affecting the pyrimidine metabolism can indirectly decrease the availability of UCK2's substrates or the feedback inhibition of the pyrimidine biosynthetic pathway, therefore affecting UCK2 activity.

The discovery of UCK2 inhibitors would involve screening for compounds that can decrease the kinase activity of UCK2. Such screening assays would measure the conversion of uridine/cytidine to UMP/CMP in the presence of potential inhibitors. Identified compounds would then be optimized for higher affinity and specificity towards UCK2. The indirect inhibitors listed in the table above target various enzymes in the nucleotide synthesis pathway, hence affecting the levels of substrates available for UCK2, or altering the feedback mechanisms that regulate pyrimidine biosynthesis. These compounds are notspecific UCK2 inhibitors; instead, they influence the broader metabolic pathways connected to UCK2's activity. The inhibition of the enzymes involved in the de novo synthesis of pyrimidines, such as dihydroorotate dehydrogenase by brequinar and leflunomide, decreases the overall pool of pyrimidine nucleotides, thus indirectly influencing UCK2 activity by reducing substrate availability.