Mcl-1 (Myeloid cell leukemia-1) is an anti-apoptotic protein, which is a member of the Bcl-2 family. Mcl-1 is involved in the regulation of apoptosis versus cell survival, and in the maintenance of cell viability but not of proliferation. Mcl-1 mediates its effects by interactions with a number of other regulators of apoptosis[3].
UMI-77 is a Mcl-1 inhibitor. In FP-based binding assays, UMI-77 potently and selectively displaced fluorescent labeled BID-BH3 peptide from Mcl-1 protein. UMI-77 bound to the BH3 binding pocket of Mcl-1 and the Ki value was 0.49 μM[4]. In a pull-down assay, starting from the concentration of 10 μM , UMI-77 dose-dependently inhibited the interactions between BL-Noxa and cellular Mcl-1 in 2LMP cell lysates. In a SPR-based binding assay, it was reported that UMI-77 dose-dependently inhibited the binding of Mcl-1 to Bax with IC50 value of 1.43 μM. UMI-77 inhibited the growth of BxPC-2 and Panc-1 cells with IC50 values of 3.4 μM and 4.4 μM, respectively[4]. UMI-77 incubated at the concentrations of 3 μM or 10 μM for 48h induced apoptosis in esophageal squamous cell carcinoma KYSE150 and KYSE510 cells, as evidenced by cleavage of caspase-3 and PARP[5].
In BxPC-3 xenograft model established in SCID mice, UMI-77 administrated i.v. at the dose of 60 mg/kg for a total of 10 doses significantly inhibited tumor growth[4].
作用机制
UMI-77 is a Mcl-1 inhibitor. Docking and spectroscopy studies revealed that UMI-77 bound to the BH3 binding pocket of Mcl-1[4].
UMI-77 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK293T
5 µM
12 hours
UMI-77 induces mitophagy without causing mitochondrial damage or apoptosis.
Nat Commun. 2020 Nov 12;11(1):5731.
ME4405 cells
4 µM
24 hours
To evaluate the apoptosis-inducing effect of UMI-77 on ME4405 cells, results showed that OVAAL overexpression conferred resistance to UMI-77-induced apoptosis.
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11661-E11670.
HCT116 cells
4 µM
24 hours
To evaluate the apoptosis-inducing effect of UMI-77 on HCT116 cells, results showed that OVAAL knockdown enhanced UMI-77-induced apoptosis.
Proc Natl Acad Sci U S A. 2018 Dec 11;115(50):E11661-E11670.
BxPC-3 cells
3.4 µM (IC50)
4 days
UMI-77 inhibits BxPC-3 cell growth with IC50 of 3.4 μM
Mol Cancer Ther. 2014 Mar;13(3):565-75.
Panc-1 cells
4.4 µM (IC50)
4 days
UMI-77 inhibits Panc-1 cell growth with IC50 of 4.4 μM
Mol Cancer Ther. 2014 Mar;13(3):565-75.
MiaPaCa-2 cells
12.5 µM (IC50)
4 days
UMI-77 inhibits MiaPaCa-2 cell growth with IC50 of 12.5 μM
Mol Cancer Ther. 2014 Mar;13(3):565-75.
AsPC-1 cells
16.1 µM (IC50)
4 days
UMI-77 inhibits AsPC-1 cell growth with IC50 of 16.1 μM
Mol Cancer Ther. 2014 Mar;13(3):565-75.
Capan-2 cells
5.5 µM (IC50)
4 days
UMI-77 inhibits Capan-2 cell growth with IC50 of 5.5 μM
Mol Cancer Ther. 2014 Mar;13(3):565-75.
MN9D cells
10 µM
4 hours
UMI-77 significantly increased the level of cleaved caspase-3 in MN9D cells and induced cell death.
Cell Death Discov. 2018 Nov 21;4:107.
N2A cells
10 µM
4 hours
UMI-77 had no significant effect on the level of cleaved caspase-3 in N2A cells.
Cell Death Discov. 2018 Nov 21;4:107.
AGS cells
8 µM (IC50)
48 hours and 72 hours
To evaluate the sensitivity of AGS cells to UMI-77, results showed that AGS cells were more sensitive to UMI-77.
Front Immunol. 2024 Jun 27;15:1428529.
MKN45 cells
125 µM (IC50)
48 hours and 72 hours
To evaluate the sensitivity of MKN45 cells to UMI-77, results showed that MKN45 cells were less sensitive to UMI-77.
Front Immunol. 2024 Jun 27;15:1428529.
NB4 cells
15–30 µM
6 hours
UMI-77 induced NOXA protein expression within 6 hours and resulted in extensive PARP cleavage in NB4 cells after 12 hours, indicating indirect inhibition of MCL1 through NOXA induction.
Cell Death Dis. 2019 Feb 22;10(3):185.
Jurkat cells
15–30 µM
6 hours
UMI-77 induced NOXA protein expression within 6 hours, indicating indirect inhibition of MCL1 through NOXA induction.
Cell Death Dis. 2019 Feb 22;10(3):185.
U937 cells
15–30 µM
6 hours
UMI-77 induced NOXA protein expression within 6 hours, indicating indirect inhibition of MCL1 through NOXA induction.
Cell Death Dis. 2019 Feb 22;10(3):185.
HeLa
5 µM
8 hours
UMI-77 promotes degradation of mitochondrial proteins without affecting endoplasmic reticulum or cytosolic markers.
Nat Commun. 2020 Nov 12;11(1):5731.
HGPS-MSCs
1 µM
UMI-77 significantly improved the mitochondrial function of HGPS-MSCs, as evidenced by decreased ROS levels, reduced mitochondrial depolarization, and increased basal and maximal respiration levels.
Aging Cell. 2024 Jun;23(6):e14143.
UMI-77 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Pitx3GFP/+ mice
Pitx3GFP/+ mice
Brain slice culture
10 µM
Overnight treatment
UMI-77 treatment increased the number of cleaved caspase-3 positive cells in brain slices of Pitx3GFP/+ mice, indicating that Mcl1 plays a crucial role in the survival of dopaminergic neurons.
Cell Death Discov. 2018 Nov 21;4:107.
APP/PS1 (C57BL/6) mice
APP/PS1 mouse model
Intraperitoneal injection
10 mg/kg
Every other day for 4 months
UMI-77 significantly improved learning and memory in APP/PS1 mice, reduced Aβ plaques and neuroinflammation, and restored mitochondrial morphology.
Nat Commun. 2020 Nov 12;11(1):5731.
Mice
LmnaG608G/G608G mice
Intragastric administration
20 mg/kg
Every other day for 5 months
UMI-77 restored mitochondrial morphology and function in HGPS mice, reduced aging-related tissue changes (such as loss of collagen fibers in the skin and fibrosis in the aorta, heart, muscles, and spleen), and significantly improved the overall health of the mice, including increased hair and weight, enhanced skeletal muscle strength, spatial working memory, and mobility, and extended the lifespan of the mice.
Aging Cell. 2024 Jun;23(6):e14143.
Mice
C57/BL6J mice
Intraperitoneal injection
5 mg/kg
Once daily for 14 days or 49 days
UMI-77 promotes mitophagy in the hippocampus of adult mice, enhances neurogenesis, and prolongs the duration of spatial memory.
CNS Neurosci Ther. 2024 Jun;30(6):e14800
SCID mice
BxPC-3 xenograft model
Intravenous injection
60 mg/kg
5 days per week for 2 weeks
UMI-77 significantly inhibited tumor growth in the BxPC-3 xenograft model
Mol Cancer Ther. 2014 Mar;13(3):565-75.
BALB/c mice
Sepsis-induced acute lung injury model
Intraperitoneal injection
7.0 mg/kg
Once daily for five days
UMI-77 significantly ameliorated histopathological changes in the lungs of mice with sepsis-induced ALI and exerted therapeutic effects by modulating key genes and metabolites.
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