NSC 185058

An inhibitor of ATG4B

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Background

NSC 185058 is an inhibitor of ATG4B, a cysteine protease that activates LC3B during the initiation of autophagy.¹ It inhibits ATG4B cleavage of LC3B-GST (IC₅₀ = 51 ?M) and reduces LC3B lipidation induced by starvation in Saos-2 cells. NSC 185058 (100 ?M) reduces starvation-induced autophagy and prevents autophagic vacuole formation in Saos-2 and MDA-MB-468 cells. It decreases phosphorylation of ribosomal protein S6 (RPS6) only marginally and does not affect phosphatidylinositol 3-kinase (PI3K) activity, indicating a direct role on ATG4B rather than through the mammalian target of rapamycin (mTOR) and PI3K signaling pathways. NSC 185058 (100 mg/kg) decreases autophagic vacuoles in vivo in mouse liver, inhibits tumor growth in an osteosarcoma nude mouse xenograft model, and decreases the number of autophagic vacuoles in osteosarcoma tumors.

1.Akin, D., Wang, S.K., Habibzadegah-Tari, P., et al.A novel ATG4B antagonist inhibits autophagy and has a negative impact on osteosarcoma tumorsAutophagy10(11)2021-2035(2014)