MRT68921 is an inhibitor of ULK1 and ULK2 (IC50s = 2.9 and 1.1 nM, respectively). Through its effects on ULK1, MRT68921 blocks autophagy in cells, driving the accumulation of stalled early autophagosomal structures.
MRT68921 dihydrochloride has been used:
- as a specific inhibitor of Unc-51-like kinase 1 (ULK1) in SH-SY5Y neuroblastoma cells
- as an inhibitor of ULK1 and ULK2 kinases in intrahepatic lymphocytes
- as a ULK1 inhibitor to test its effect on attenuation of autophagosome accumulation in ubiquitin-specific peptidase 24 (USP24)knockdown containing human neuroglioma H4 cells
MRT68921 is cytotoxic and acts on oxidative stress signals to kill cancer cells, making it an effective tumor therapy agent.
mrt68921 was identified to be relatively specific, but still could inhibit a number of kinases by over 80%. most importantly, tbk1/ikk as well as the ampk-related kinases were still found to be targeted. moreover, by using lkb1 knock-out mefs, it was found that lc3 flux was comparable with matched, wild-type mefs and could be inhibited to the same extent in the treatment with mrt68921. thus, these kinases are suggested to be not the target of mrt68921 in blocking autophagy. in addition, mrt68921 was found to be able to block the wt-restored atg13 phosphorylation and autophagy, which was similar to cells expressing endogenous ulk1. in contrast, in cells expressing a similar level of m92t ulk1, mrt68921 could not reduce either atg13 phosphorylation or lc3 flux, which indicated that mrt68921 was truly able to block autophagy via ulk1 kinase inhibition [1].
2.9 nm and 1.1 nm for ulk1 and ulk 2, respectively.
[1] petherick kj, conway oj,mpamhanga c,osborne sa,kamal a,saxty b,ganley ig. pharmacological inhibition of ulk1 kinase blocks mammalian target of rapamycin (mtor)-dependent autophagy. j biol chem.2015 may 1;290(18):11376-83.
