LONP1 inhibitor

LONP1 inhibitors are a class of research-stage small molecules that target Lon Protease Homolog 1 (LONP1), an ATP-dependent mitochondrial AAA+ serine protease. LONP1 is responsible for maintaining mitochondrial homeostasis by degrading damaged or misfolded proteins and supporting mitochondrial DNA maintenance. Elevated LONP1 expression is linked to cancer cell proliferation, metabolic reprogramming (transitioning from glycolysis to oxidative phosphorylation), and resistance to apoptosis and chemotherapy (e.g., temozolomide in glioblastoma). Several research groups have developed LONP1 inhibitors, including boronic acid-based compounds from the Genomics Institute of the Novartis Research Foundation, triterpenoids such as CDDO-Me (bardoxolone methyl) and CDDO-Im, and the small molecule BT317. These agents are being investigated for the treatment of various malignancies, including glioblastoma, malignant astrocytoma, colorectal cancer, melanoma, and multiple myeloma.