Nnc-51 like autophagy initiating kinase 1 (ULK1) is a serine/threonine kinase that works as a part of a complex with binding partners ATG13, RB1CC1, and ATG101 in autophagy induction. ULK-101 is a potent, selective inhibitor of ULK1 with an IC50 value of 8.3 nM in vitro, whereas the inhibitory effect of ULK-101 on ULK2 is weaker with an IC50 value of 30 nM. In 293FT cells expressing ULK1, ULK-101 at the doses of 60 – 1000 nM dose-dependently inhibited Ser15 phosphorylation with an EC50 value of 390 nM. In U2OS cells stably expressing omegasome marker, EGFP-DFCP1, 2.5-h treatment with 5 μM ULK-101 completely inhibited the formation of DFCP1-positive structures induced by AZD8055 (100 nM). ULK-101 at the same dose also strongly reduced AZD8055-induced phagophore formation. Incubation of U2OS cells with ULK-101 (300 – 5000 nM) for 3 hours reduced BafA1-induced LC3B-II accumulation in a concentration-dependent manner with an EC50 value of 700 nM. Also, ULK-101 treatment led to a 6-fold reduction of BafA1-induced accumulation of LC3B-positive vesicles as compared to the vehicle control. ULK-101 reduced cell viability of U2OS cells when they were cultured in both Optistarve (OS) and full growth media (FM) with EC50 values of 6.3 and 22.3 μM, respectively. Furthermore, KRAS mutant or amplified non-small-cell lung cancer cell lines demonstrated a 5-fold increase in ULK-101 sensitivity when cultured in OS compared with FM[1].
作用机制
ULK-101 is a ULK1 inhibitor. It blocks the autophagy induction and suppresses autophagic flux in response to multiple stimuli.
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