TFEB activator 1 is an orally effective, mTOR-independent activator of TFEB. It significantly promotes the nuclear translocation of Flag-TFEB with an EC50 of 2167 nM and enhancesautophagy without inhibiting themTOR pathway and has the potential for neurodegenerative diseases treatment. It also shows cytotoxic effect on HeLa, K562, MCF-7 and MDA-MB-231 cancer cell lines.
Activation of TFEB (transcription factor EB), a master regulator of autophagy and lysosomal biogenesis, can ameliorate neurotoxicity and rescue neurodegeneration in animal models.
TFEB activator 1 is a novel MTOR-independent TFEB activator. It significantly promoted phosphorylation of RPS6KB1 and MTOR, indicating that C1 enhanced autophagy without inhibiting the MTOR pathway. TFEB activator 1 (1 μM; 12 h) potently induced nuclear translocation of endogenous TFEB in N2a cells and it significantly promoted the nuclear translocation of Flag-TFEB with an EC50 value of 2167 nM. The dissociation constant (KD) of C1 to TFEB was determined to be 2.53 μM. In HeLa cells stably expressing Flag-TFEB, the levels of YWHA coimmunoprecipitated with Flag-TFEB significantly decreased after TFEB activator 1 (1 μM; 12 h) treatment compared with the control, suggesting that TFEB activator 1 could reduce TFEB-YWHA interaction independently of MTOR activity. TFEB activator 1 treatment dose-dependently increases the levels of LC3-II and SQSTM1/p62 (sequestosome 1) in N2a cells, and the effects require at least 9 h of treatment. However, 6 h of TFEB activator 1 treatment was sufficient to significantly promote TFEB nuclear translocation, indicating a delayed autophagy response via TFEB activation. The protein level of SQSTM1 (a target gene of TFEB) was significantly decreased by TFEB activator 1 (1 μM; 12 h), indicating that it enhances autophagic degradation of SQSTM1. Short-term oral administration of TFEB activator 1 (10 mg/kg and 25 mg/kg) dose-dependently increased the expression of LC3B-II and TFEB in the liver, frontal cortex and striatum of the brain. Meanwhile, TFEB activator 1 treatment dose-dependently increased the expression of LAMP1 in the frontal cortex[1].
作用机制
The binding site of TFEB activator 1 is likely located at the N-terminal Gly and Ala-rich domain of TFEB[1].
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