DNL-I

DNL-I is a novel small molecule inhibitor of de novo lipogenesis (DNL) currently in preclinical development for the treatment of multiple myeloma (MM). It specifically targets the metabolic vulnerability of myeloma cells by downregulating the expression of key enzymes in the fatty acid synthesis pathway, namely acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN). This disruption of lipid homeostasis leads to dose-dependent apoptosis in both treatment-sensitive and proteasome inhibitor-resistant MM cell lines. Research indicates that DNL-I's cytotoxic effects are driven by the depletion of endogenous lipids required for membrane biogenesis and cellular signaling, as exogenous lipid supplementation can fully reverse its activity. Beyond lipid metabolism, DNL-I treatment has been shown to alter amino acid metabolism, the TCA cycle, and sphingolipid pathways, highlighting its potential to overcome drug resistance in relapsed/refractory multiple myeloma.