EN6

EN6 is an activator of autophagy.¹ It inhibits mammalian target of rapamycin complex 1 (mTORC1) signaling by binding covalently to cysteine 277 of the ATP6V1A catalytic subunit of the lysosomal vacuolar ATPase (v-ATPase) and impairing v-ATPase coupling with Rag GTPases. It is selective for inhibition of mTORC1 over mTORC2 signaling. EN6 increases lysosome acidification and increases cellular clearance of TDP-43 protein aggregates, which are a pathological feature of several neurodegenerative diseases, in a v-ATPase-dependent manner in U2OS osteosarcoma cells. It also inhibits mTORC1 signaling and enhances autophagy in mouse skeletal muscle and heart when administered at a dose of 50 mg/kg.

1.Chung, C.Y.-S., Shin, H.R., Berdan, C.A., et al.Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibitionNat. Chem. Biol.15776-785(2019)