TS Inhibitors

The class of TS inhibitors comprises diverse chemicals that target thymidylate synthase (TS), a pivotal enzyme involved in thymidine biosynthesis, DNA replication, and cellular proliferation. These inhibitors can be categorized into two groups: direct and indirect. Direct TS inhibitors, such as 5-Fluorouracil (5-FU), Raltitrexed, Pemetrexed, Methotrexate, 6-Mercaptopurine, and 5-Fluoro-2'-deoxyuridine (FdUrd), exert their effects by directly interfering with the enzymatic activity of TS. They disrupt thymidine biosynthesis and DNA replication through various mechanisms. Some compete with TS substrates, effectively hindering its catalytic function. Others, like FdUrd, become incorporated into nucleic acids during replication, causing structural damage to DNA and impeding cellular growth. Indirect TS inhibitors, which include 6-Thioguanine, Tipiracil, Aminopterin, Edatrexate, Ralimetinib (LY2228820), and Tipifarnib (R115777), operate through alternative pathways to influence TS activity. These compounds have diverse modes of action. Some, like 6-Thioguanine, disrupt purine or folate metabolism, indirectly perturbing the balance of nucleotides within the cell. This disruption ultimately hampers TS function and inhibits thymidine biosynthesis. Others, such as Ralimetinib and Tipifarnib, modulate signaling pathways like MAPK/ERK and Ras/MAPK, respectively. By targeting these pathways, these inhibitors downregulate TS expression, leading to a reduction in thymidine production and impairing DNA replication. In summary, the class of TS inhibitors encompasses a wide range of chemicals that directly or indirectly impact the function of thymidylate synthase. These compounds play essential roles in disrupting thymidine biosynthesis, DNA replication, and cellular proliferation.