MRT68921 is a potent dual inhibitor of ULK1 and ULK2 with IC50 values of 2.9nM and 1.1nM, respectively [1]. MRT68921 can induce the lipidation of LC3-II, the formation of GFP/LC3 aggregates, leading to an increase in the phosphorylation level of AMPKα (T712) and promoting cellular apoptosis [2]. MRT68921 has been widely used to inhibit the growth of cancer cells and to develop new combined therapies for the elimination of tumor cells[3].
In vitro, MRT68921 treatment for 20 hours significantly inhibited the viability of THP-1 cells and HL60, with the IC50 values being 3.6μM and 2.6μM, respectively[4]. Treatment with 10μM MRT68921 for 12 hours can induce spindle microtubule disarray and abnormal mitosis in HeLa cells[5]. Treatment with 2μM MRT68921 for 24 hours inhibited autophagy in serum-starved p53−/− mouse embryonic stem cells (mESCs) and increased caspase activity[6].
In vivo, MRT68921 treatment via intravenous injection at a dose of 20mg/kg/day for 7 consecutive days significantly inhibited the metastasis of cancer cells in the 4T1 murine breast cancer model, reduced tumor burden, and improved the survival rate of the mice[7]. Intraperitoneal injection of MRT68921 twice a week at a dose of 20mg/kg, in combination with SAR405 (20mg/kg; i.p.) and paclitaxel (5mg/kg; i.p.) for 21 days, significantly inhibited tumor growth in the MDA-MB231 xenograft mouse model [8].
References:
[1] Petherick K J, Conway O J L, Mpamhanga C, et al. Pharmacological inhibition of ULK1 kinase blocks mammalian target of rapamycin (mTOR)-dependent autophagy[J]. Journal of Biological Chemistry, 2015, 290(18): 11376-11383.
[2] Jang J, Jeung H, Seol S Y, et al. Inhibition of Unc-51-like Kinase 1 (ULK1) with novel small molecular inhibitor MRT68921 preferentially induces apoptosis and autophagy in FLT3-ITD-mutated acute myeloid leukemia[J]. Blood, 2018, 132: 3499.
[3] Xu Z, Bao J, Jin X, et al. The effects of cinobufagin on hepatocellular carcinoma cells enhanced by MRT68921, an autophagy inhibitor[J]. The American Journal of Chinese Medicine, 2023, 51(06): 1595-1611.
[4] Yang W, Li Y, Liu S, et al. Inhibition of ULK1 promotes the death of leukemia cell in an autophagy irrelevant manner and exerts the antileukemia effect[J]. Clinical and Translational Medicine, 2021, 11(1): e282.
[5] Ji X, Zhang X, Li Z. ULK1 inhibitor induces spindle microtubule disorganization and inhibits phosphorylation of Ser10 of histone H3[J]. FEBS open bio, 2020, 10(11): 2452-2463.
[6] Vorobev M L, Alhasan B A, Suvorova I I. The upregulation of Ulk1-dependent autophagy does not require the p53 activity in mouse embryonic stem cells[J]. Biochemical and biophysical research communications, 2021, 552: 78-83.
[7] Chen Y, Xie X, Wang C, et al. Dual targeting of NUAK1 and ULK1 using the multitargeted inhibitor MRT68921 exerts potent antitumor activities[J]. Cell death & disease, 2020, 11(8): 712.
[8] Abd El-Aziz Y S, du Toit-Thompson T, McKay M J, et al. Novel combinatorial autophagy inhibition therapy for triple negative breast cancers[J]. European Journal of Pharmacology, 2024, 973: 176568.
MRT68921是一种强效的ULK1和ULK2双重抑制剂，对ULK1和ULK2的IC50值分别为2.9nM和1.1nM[1]。MRT68921可诱导LC3-II的脂化、GFP/LC3聚集体的形成，导致AMPKα(T712)磷酸化水平升高，并促进细胞凋亡[2]。MRT68921已被广泛用于抑制癌细胞生长，并开发用于消除肿瘤细胞的新型联合疗法[3]。
在体外，MRT68921处理20小时显著抑制了THP-1细胞和HL60细胞的活力，IC50值分别为3.6μM和2.6μM[4]。使用10μM的MRT68921处理HeLa细胞12小时，可诱导纺锤体微管紊乱和异常有丝分裂[5]。使用2μM的MRT68921处理经血清饥饿的p53−/−小鼠胚胎干细胞(mESCs)24小时，可抑制自噬并增加caspase活性[6]。
在体内，连续7天静脉注射20mg/kg/day剂量的MRT68921，显著抑制了4T1小鼠乳腺癌模型中的癌细胞转移，减少了肿瘤负荷，并提高了小鼠的存活率[7]。每周两次腹腔注射20mg/kg剂量的MRT68921，联合SAR405（20mg/kg；i.p.）和paclitaxel（5mg/kg；i.p.），持续21天，显著抑制了MDA-MB231异种移植小鼠模型中的肿瘤生长[8]。