NPD-389

NPD-389 is a small molecule, isoform-nonselective inhibitor of mitochondrial malic enzymes, specifically targeting ME1, ME2, and ME3. Mitochondrial malic enzyme 2 (ME2) is frequently overexpressed in various malignancies, including melanoma, pancreatic, and lung cancers, where it facilitates metabolic reprogramming to support rapid cell proliferation and survival by producing pyruvate and NAD(P)H. NPD-389 exerts its inhibitory effect by binding to the enzyme in a metal-coordinating mode, which captures the protein in a specific, targetable conformation. Preclinical evaluations in melanoma and triple-negative breast cancer (TNBC) cell lines have demonstrated that NPD-389 significantly reduces tumor cell proliferation, highlighting its potential as a lead compound for the development of metabolism-directed cancer therapies.