1808714-73-9

EN6 is a small-molecule in vivo autophagy activator that covalently targets cysteine 277 in the ATP6V1A subunit of the lysosomal v-ATPase. EN6-mediated modification of ATP6V1A uncouples v-ATPase from Rag, leading to inhibition of mTORC1 signalling, increased lysosomal acidification, and activation of autophagy. EN6 also scavenges TDP-43 aggregates (causative agents of frontotemporal dementia) in a lysosome-dependent manner[1].

EN6 is an autophagy activator th at simultaneously upregulates lysosomal vacuolar H(+)-ATPase (v-ATPase) activity and induces its decoupling from the Rag GTPases by covalently targeting v-ATPase subunit ATP6V1A Cys277. EN6 blocks mTORC1 lysosomal recruitment & activation (1-4 hr 25 μM EN6 pretreatment prior to 10-min amino acids (AA) stimulation of AA-starived HEK293) and clears cellular TDP-43 aggregates (25 μM; U2OS with inducible TDP-43). When administered in mice in vivo (50 mg/kg ip.)EN6 inhibits mTORC1 signaling and activates autophagy in both skeletal muscle and heart tissue. Unlike bafilomycin A1 (BafA1)EN6 activatesbut not inhibits v-ATPase catalytic activity.

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[1] Chung CY, et al. Covalent targeting of the vacuolar H+-ATPase activates autophagy via mTORC1 inhibition. Nat Chem Biol. 2019 Aug;15(8):776-785. DOI:10.1038/s41589-019-0308-4