TR-65

TR-65 is a highly potent, small-molecule imipridone-derived agonist of the mitochondrial matrix protease caseinolytic peptidase P (ClpP). Developed by Madera Therapeutics as a second-generation analogue of ONC201, TR-65 binds directly to ClpP with nanomolar affinity, hyperactivating its peptidase activity. This hyperactivation leads to the unregulated degradation of essential mitochondrial proteins, such as mitochondrial transcription factor A (TFAM), which in turn disrupts mitochondrial protein homeostasis, depletes mitochondrial DNA (mtDNA), and impairs oxidative phosphorylation (OxPhos). Preclinical studies have demonstrated that TR-65 is significantly more potent than ONC201 in inhibiting cell proliferation and suppressing breast cancer stem cell (CSC) function both in vitro and in vivo, particularly in triple-negative breast cancer (TNBC) models.

Other names

TR65TR-65TR 65