ATG4B is a cysteine protease that activates LC3 for lipidation and recent studies suggest that it may be another promising target to inhibit autophagy upstream of the lysosome. Consistent with this idea, several ATG4B inhibitors have been developed including FMK-9a, NSC185058, and S130. S130 have demonstrated significant in vivo activity against colon tumor. Today, We will introduce S130.

S130 is a ATG4B inhibitor that inhibits autophagy

S130 is a high affinity, selective inhibitor of ATG4B (a major cysteine protease) with an IC50 of 3.24 µM. It suppresses autophagy flux. Firstly, S130 suppresses autophagy and activates apoptosis by inhibiting ATG4B, leads to enhanced cytotoxicity. Secondly, S130 (10 μM; 6 hours) suppresses autophagy at the early LC3 priming step or late autolysosome degradation stage. Besides, S130 accumulates autolysosomes with more lipidated LC3. What’s more, S130 (0-25 μM; 48 hours) induces cell death through inhibiting the activity of ATG4B at a dose higher than 6.3 µM. And such cytotoxicity might not cause cell death through necroptosis. Furthermore, Nutrient deprivation enhances S130-induced cytotoxicity. It (0-10μM; 24 hours) suppresses approximately 79% of the cleavage of full-length LC3-GST at the 10 µM, while no substrates were processed in ATG4B KO cells. S130 displays obvious inhibitory effects on ATG4B. Finally, S130 (20 mg/kg; i.p.; daily; 3 weeks) suppresses tumor growth, and shows an efficient in vivo antitumor effect with a sound safety on vital organs.

All in all, S130 is a selective ATG4B inhibitor for cancers research.

References:

[1] Jones TM, et al. Cancers (Basel). 2020 May 7;12(5):1185.

[2] Fu Y, et al. Autophagy. 2019 Feb;15(2):295-311.