OMA1 activator BTM-3566

An orally bioavailable activator of the mitochondrial protease OMA1, with potential antineoplastic activity. Upon oral administration, OMA1 activator BTM-3566 activates OMA1. This leads to OMA1-dependent cleavage of DAP3-binding cell death enhancer 1 (DELE1) and mitochondrial dynamin-like GTPase OPA1, mitochondrial fragmentation, and activation of the eIF2alpha-kinase heme-regulated inhibitor (HRI), and induces cyclic AMP-dependent transcription factor ATF-4-mediated integrated stress response (ISR) and hyperactivates mitochondrial ISR, which result in apoptosis. OMA1 plays a key role in the activation of the ISR pathway in response to hypoxia, amino acid deprivation, and accumulation of misfolded proteins. While ISR promotes the adaptation of tumor cells to hypoxic stress, prolonged activation of ISR induces apoptosis.