BOC Sciences is a pioneer of ADCs cytotoxin discovery and manufacture, providing the most comprehensive list of cytotoxic products globally. We are committed to providing competitive prices and timely delivery of our products with guaranteed quality and recognized quality. Furthermore, we offer our customers with comprehensive one-stop-shop of all aspects in ADC development and evaluation. As a key enzyme of folate metabolism, dihydroforate reductase (DHFR) catalyzes the reduction of dihydrofolate to tetrahydrofolate using NADPH as a cofactor. Since tetrahydrofolate is essential for DNA synthesis, cell growth and proliferation, inhibition of DHFR results in a depletion of the reduced folate pools, inhibition of DNA synthesis, and cell death. Therefore, dihydrofolate reductase (DHFR) is a prominent molecular target in antitumor, antibacterial, antiprotozoan, and immunosuppressive chemotherapies.
Comprehensive one-stop antibody-drug conjugate service platform
More than 1000+ high-purity products in inventory
Warehouses in multiple cities to ensure fast delivery
mg to kg
Qualified facilities & equipment of cGMP laboratory
24/7 Technical Support
Strict process parameter control to ensure product quality
Dihydrofolate reductase (DHFR) is a key enzyme in the production of thymidine. Its role in thymidine biosynthesis is the reduction of dihydrofolate to tetrahydrofolate using the cofactor NADPH. Following this reduction, tetrahydrofolate is methenylated to form methylene-tetrahydrofolate, which then methylates deoxyuridine monophosphate (dUMP) to give TMP in a reaction catalysed by thymidylate synthase (TS). During this reaction, methylene-tetrahydrofolate is converted back to dihydrofolate, completing the cycle. Therefore, inhibition of DHFR prevents biosynthesis of thymidine, and as a consequence, DNA biosynthesis. In addition, inhibition of DHFR probably leads to a buildup in levels of dUMP and hence to a biosynthetic precursor, deoxyuridine triphosphate. High levels of deoxyuridine triphosphate leads to incorporation of uracil into DNA to levels beyond which the DNA repair enzymes (uracil-DNA-glycosylase) can cope, leading to cell death.
Fig. 1. α-Carbon representation of human DHFR complexed with NADPH and MOT (Vitamins and Hormones, Volume 79).
Antifolates are the oldest of the antimetabolite class of anticancer drugs and have been used in the clinic for more than four decades. The first clinically useful antifolate was aminopterin, a tight binding inhibitor of DHFR. The classically taught mechanism of action for methotrexate (MTX) is inhibition of dihydrofolate reductase (DHFR) to deplete cellular pools of tetrahydrofolate and stop the production of thymidylate. Cells lacking adequate thymidine are unable to synthesize DNA, which results in the arrest of cellular proliferation. The combined effect is thought to lead to the demise of rapidly dividing cell populations either through apoptosis or autophagy. In cancer therapy, sustained maximal DHFR inhibition is targeted and important for several reasons. First, it provides steady inhibition of DNA synthesis, and, second, it minimizes the risk of developing resistance to MTX. With only 1% of the average cellular DHFR concentration required to maintain a sufficient reserve of reduced folate coenzymes, high doses of MTX are required to achieve this effect and are frequently limited by toxicities. BOC Sciences offers the dihydrofolate reductase inhibitor Methotrexate disodium to support your ADC development.