TH9619

TH9619 is a **novel, small-molecule inhibitor** that targets the dehydrogenase and cyclohydrolase activities of both **MTHFD1** and, selectively, the **nuclear form of MTHFD2**, both of which are enzymes in the one-carbon folate pathway crucial for nucleotide biosynthesis in cancer metabolism[1][4][5]. TH9619 primarily inhibits MTHFD1 in the cytosol and nuclear MTHFD2, but does not enter mitochondria to affect mitochondrial MTHFD2[1]. Its mechanism leads to **“folate trapping”**, causing the accumulation of 10-formyl-tetrahydrofolate and depletion of downstream thymidylate, resulting in replication stress, DNA damage, and selective killing of MTHFD2-expressing cancer cells[1][2][4]. Preclinical studies demonstrate potent anti-tumor activity in vitro and in xenograft models of hematological and solid cancers, especially B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL), with minimal observed toxicity[2][4].