mthfd2

DS18561882 is an orally available, selective and potent inhibitor of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) with antitumor activity, inhibits MTHFD1 activity and can be used in the study of breast cancer.

DS44960156 is a novel selective inhibitor of methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) that inhibits both MTHFD2 and MTHFD1 and can be used in cancer research.

MTHFD2-IN-5 (Compound 16e) is a selective inhibitor of MTHFD2 with an IC50 of 66 nM. It inhibits the proliferation of MOLM-14 cells with a GI50 of 720 nM and demonstrates antitumor activity in mouse models.

MTHFD2-IN-6 (compound 41) is a potent and selective inhibitor of MTHFD2, displaying inhibitory activity against both MTHFD1 and MTHFD2 with IC50 values of 19.05 μM and 1.46 μM respectively.

MTHFD2-IN-7 is an orally active and selective inhibitor of MTHFD2, exhibiting IC50 values of 0.038 μM for human-derived hMTHFD1 and 7.44 μM for hMTHFD2. It operates by binding to the substrate binding site of MTHFD2 while maintaining interaction with NAD+. Validated by TSA and DARTS experiments, MTHFD2-IN-7 effectively binds its target protein and demonstrates Caco-2 permeability and liver microsomal metabolic stability. In mice, it shows favorable pharmacokinetic properties. Furthermore, MTHFD2-IN-7 significantly inhibits cancer cell proliferation and reduces tumor size, making it a promising small molecule tool for acute myeloid leukemia research.

MTHFD2-IN-1 (compound 12) is a potent inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2) [1].

MTHFD2-IN-2 (compound 13) is a potent inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2) [1].

MTHFD2-IN-3 (compound 10), a potent inhibitor of methylenetetrahydrofolate dehydrogenase (MTHFD2), demonstrates significant efficacy in obstructing the activity of this enzyme [1].

MTHFD2-IN-4, a tricyclic coumarin derivative, serves as a potent inhibitor of MTHFD2 and has applications in cancer research [1].

MTHFD2-IN-4 sodium, a potent inhibitor of MTHFD2 and a tricyclic coumarin derivative, is applicable in cancer research [1].

TH9028 is an inhibitor targeting MTHFD1, MTHFD2, and MTHFD2L, with IC50 values against the human-derived targets of 0.5 nM (MTHFD1), 11 nM (MTHFD2), and 27 nM (MTHFD2L), respectively. This compound binds to the substrate-binding region of the target enzymes, forming hydrogen bonds and other interactions with key amino acid residues, while also inducing conformational changes in the loop 1 region of the enzyme. Functionally, TH9028 slows down the progression of replication forks, induces replication stress, causes cell cycle arrest at the S phase, promotes apoptosis, inhibits thymidine synthesis, and leads to the misincorporation of uracil into DNA. In acute myeloid leukemia and T-ALL cells, TH9028 exhibits antiproliferative activity, while its effects on non-transformed cells are relatively weak. Therefore, TH9028 can be used in research related to acute myeloid leukemia.

TH9028 TFA is an effective MTHFD2 inhibitor (IC50=11 nM) that suppresses proliferation in HL-60 cells, AML cells, and T-ALL Jurkat cells.

LY 345899 is a folate analog that inhibits methylenetetrahydrofolate dehydrogenase and MTHFD2, with IC50 values of 96 nM and 663 nM, respectively, and a Ki of 18 nM for MTHFD1.

Anticanceragent 310 is an antitumor compound that releases nitric oxide to induce mitochondrial ROS outburst, leading to mitochondrial dysfunction and activating the Bax/Bcl-2-Cyt c-Caspase-9/Caspase-3 apoptosis pathway. It also reduces SHMT2 and MTHFD2 levels, decreasing the NADPH/NADP+ and GSH/GSSG ratios, thereby disrupting redox homeostasis and increasing intracellular ROS accumulation. Anticanceragent 310 is useful for gastric cancer research.

MTHFD1/2-IN-1 is an orally active dual inhibitor of MTHFD1 and MTHFD2, exhibiting IC50 values of 0.26 μM and 0.031 μM for human MTHFD1 and MTHFD2, respectively. It disrupts one-carbon metabolism by inhibiting the dehydrogenase activity of MTHFD1 and both the dehydrogenase and cyclohydrolase activities of MTHFD2, thereby impairing nucleotide biosynthesis and redox homeostasis in cancer cells. This compound demonstrates good Caco-2 permeability and hepatic microsome metabolic stability. Furthermore, MTHFD1/2-IN-1 shows significant anti-leukemia activity, reducing the viability of various leukemia cells and inhibiting tumor growth in mouse models of acute myeloid leukemia (AML).

TH9619 is an effective inhibitor of both dehydrogenase and cyclohydrolase activities in MTHFD1 and MTHFD2 (IC50=47 nM). It induces folate trapping and cell cycle arrest, thereby selectively killing cancer cells expressing MTHFD2.