PGDH Inhibitors

PGDH inhibitors are a class of compounds that target 3-Phosphoglycerate Dehydrogenase, an enzyme crucial for serine biosynthesis. This enzyme catalyzes the first step in the phosphorylated pathway of serine biosynthesis, converting 3-phosphoglycerate into 3-phosphohydroxypyruvate. PGDH is allosterically regulated and can be inhibited by various chemical compounds, which either bind directly to the enzyme's active site or interact with regulatory sites. Direct inhibitors of PGDH, such as CBR-5884 and NCT-503, typically function by binding to the enzyme's active or cofactor binding sites. CBR-5884, for instance, binds to the NAD+-binding domain of PGDH, effectively inhibiting the enzyme's function and reducing serine synthesis in cancer cells. This mode of inhibition is crucial for understanding the role of serine in various metabolic pathways, particularly in rapidly proliferating cells like cancer cells. On the other hand, NCT-503 targets the active site, preventing the conversion of substrate into product. These inhibitors are often used in research to understand the metabolic requirements of cells and the role of serine in cellular proliferation and survival. In addition to direct inhibitors, several compounds indirectly influence PGDH activity. For example, Erastin and Sulfasalazine affect cellular redox status, which in turn can modulate the activity of PGDH. Methotrexate, a well-known chemotherapy agent, indirectly impacts PGDH through its inhibition of dihydrofolate reductase, which plays a role in folate metabolism and indirectly affects serine synthesis. These indirect inhibitors provide insights into the broader metabolic networks and regulatory mechanisms in which PGDH participates.