(2014-06-06) Tan, Justin; Zon, Leonard Ira; Bradner, James; Look, A; Cantor, Alan
Recent evidence suggests that leflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, disrupts neural crest development and melanoma pathogenesis via inhibiting transcription elongation. DHODH is an enzyme in the pyrimidine biosynthetic pathway and inhibition of this enzyme by leflunomide triggers a low nucleotide state. Leflunomide effectively ablates the neural crest lineage in embryonic zebrafish, preventing the formation of mature melanocytes, among other neural crest lineages. This drug also effectively suppresses melanoma and is in a clinical trial, administered in combination with the BRAF inhibitor vemurafenib, for metastatic melanoma. Despite knowing that leflunomide targets transcription elongation, the mechanism by which low nucleotides directly regulates transcription is unknown.
