ATG4 or autophagins are a class of cytosolic cysteine proteases that cleave ATG8 family proteins. ATG4 plays essential roles in the formation and maturation of autophagosomes[2]. FMK 9a is a potent inhibitor of ATG4B and ATG4A with IC50 values of 0.23 and 0.36 μM, respectively. FMK 9a exhibits strong binding affinity for both full-length ATG4B and ATG4BC74S with KDs of 3.89 μM and 3.24 μM, respectively. In vitro, FMK 9a (1 μM) could almost entirely inhibit ATG4B activity in HeLa cells in a very short time. FMK 9a could efficiently accumulate LC3-II in dose-dependent manner both in HeLa and MEF cells. Meanwhile, FMK 9a also induced LC3-II accumulation in a time-dependent manner and showed the best effect at 6 hrs[3]. FMK 9a exhibits moderate solubility and high human and mouse liver microsome clearances of 13.9 and 70 mL/min/kg, respectively[2].
作用机制
FMK 9a forms an irreversible covalent bond with the more reactive thiol group of Cys74 located at the catalytic site of ATG4B[2].
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