UNC0379 is the first substrate-competitive inhibitor of SETD8 with IC50 value of 7.3μM, selective for SETD8 over 15 other methyltransferases[4].
作用机制
UNC0379 is a substrate-competitive SETD8 inhibitor. The quinazoline rings of the compound fill the space that in the SETD8-SAH complex is occupied by the amino group of the substrate lysine side chain.[3]
UNC0379 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Mouse 5T33MMvv cells
2.5 µM to 40 µM
24 hours
Evaluate the toxic effects of UNC-0379 on murine MM cell models, showing a significant reduction in cell viability.
Clin Epigenetics. 2021 Sep 16;13(1):174.
Primary MM cells
1 µM, 2.5 µM, 5 µM
4 days
Assess the toxic effects of UNC-0379 on primary MM cells, demonstrating a significant reduction in malignant plasma cell numbers.
Clin Epigenetics. 2021 Sep 16;13(1):174.
Human myeloma cell lines (HMCLs)
1 µM, 2.5 µM, 5 µM
4 days
Evaluate the toxic effects of UNC-0379 on HMCLs, showing dose-dependent inhibition of cell growth.
Clin Epigenetics. 2021 Sep 16;13(1):174.
NHLF
10 µM
48 hours
UNC0379 was sensitive to the upregulation of ED-A-FN in NHLF, suggesting that SET8 may be involved in TGF-β1-induced FMD in normal fibroblasts.
Front Mol Biosci. 2020 Aug 5;7:192.
IPF-MyoF
10 µM
48 hours
UNC0379 significantly suppressed the expression of α-SMA and ED-A-FN, reversing the phenotype of IPF-MyoF.
Front Mol Biosci. 2020 Aug 5;7:192.
TYK-nu
10 µM
72 hours
Inhibition of cell proliferation and induction of apoptosis
Biomolecules. 2020 Dec 16;10(12):1686.
OVCAR3
10 µM
96 hours
Inhibition of cell proliferation and induction of apoptosis
Biomolecules. 2020 Dec 16;10(12):1686.
JHOS3
10 µM
96 hours
Inhibition of cell proliferation and induction of apoptosis
Biomolecules. 2020 Dec 16;10(12):1686.
MDA-MB-231 cells
5 or 10 µM
48 hours
To verify the inhibitory effect of UNC0379 on the proliferation of breast cancer cells, the results showed that as the concentration of UNC0379 increased, the proliferation of MDA-MB-231 cells was more strongly inhibited.
Oncol Rep. 2024 Aug;52(2):110.
CR-CSphCs
0.5, 1, 2, 4, 8 µg/ml
48 hours
Evaluating the effect of UNC0379 on CR-CSphCs, results showed that UNC0379 treatment led to a gradual decrease in p53K382me1 and H4K20me1 protein levels while restoring p53 and p21 levels and reducing colony-forming capability.
Mol Cancer. 2025 Mar 31;24(1):102.
THP1 cells
0.5, 1, 2, 4, 8 µg/ml
48 hours
Evaluating the effect of UNC0379 on THP1 cells, results showed that UNC0379 treatment led to a gradual decrease in p53K382me1 and H4K20me1 protein levels while restoring p53 and p21 levels.
Mol Cancer. 2025 Mar 31;24(1):102.
BMSC cells
2 µM
48 hours
Evaluate the cytotoxicity of UNC0379 on BMSC cells, results showed BMSC cells were not sensitive to UNC0379.
Cell Death Dis. 2024 Jul 10;15(7):494.
SK-NEP-1 cells
2 µM
48 hours
Evaluate the cytotoxicity of UNC0379 on SK-NEP-1 cells, results showed SK-NEP-1 cells were sensitive to UNC0379.
Cell Death Dis. 2024 Jul 10;15(7):494.
SKNMC cells
2 µM
48 hours
Evaluate the cytotoxicity of UNC0379 on SKNMC cells, results showed SKNMC cells were sensitive to UNC0379.
Cell Death Dis. 2024 Jul 10;15(7):494.
Glioblastoma primary cells
5 µM
48 hours
SETD8 inhibition resulted in p53 protein stabilization and p21 accumulation
Cell Death Dis. 2023 Sep 27;14(9):638.
SW1088 cells
5 µM
48 hours
SETD8 inhibition resulted in increased DNA damage, Chk1 phosphorylation, and G2/M arrest
Cell Death Dis. 2023 Sep 27;14(9):638.
U251 cells
5 µM
48 hours
SETD8 inhibition resulted in increased DNA damage, Chk1 phosphorylation, and G2/M arrest
Cell Death Dis. 2023 Sep 27;14(9):638.
LN-18 cells
5 µM
48 hours
SETD8 inhibition resulted in increased DNA damage, p53 protein stabilization, p21 accumulation, and G1/S arrest
Cell Death Dis. 2023 Sep 27;14(9):638.
U87MG cells
5 µM
48 hours
SETD8 inhibition resulted in increased DNA damage, p53 protein stabilization, p21 accumulation, and G1/S arrest
Cell Death Dis. 2023 Sep 27;14(9):638.
CaSki cells
9.97 ± 0.58 µM (IC50)
48 hours
UNC0379 enhanced the sensitivity of CaSki cells to cisplatin, reducing the IC50 value.
Cell Biosci. 2023 Jun 12;13(1):107.
SiHa cells
8.73 ± 0.49 µM (IC50)
48 hours
UNC0379 enhanced the sensitivity of SiHa cells to cisplatin, reducing the IC50 value.
Cell Biosci. 2023 Jun 12;13(1):107.
SK-N-BE2C (MYCN-amp)
0.1-30 µM
7 days
UNC0379 exhibited antitumor activity in MYCN-amplified NB cell lines with IC50 values ranging from 0.64 to 7 μM.
Cancer Cell. 2017 Jan 9;31(1):50-63.
SY5Y (MYCN-WT)
0.1-30 µM
7 days
UNC0379, a selective, substrate-competitive inhibitor of SETD8, was one of the most active compounds, exhibiting a relatively low average IC50 (2 μM) and a highly significant p value for the In Vitro Therapeutic Index (IVTI) across the 8 NB cell lines compared with control cell lines.
Cancer Cell. 2017 Jan 9;31(1):50-63.
Huh-7 cells
5 µM and 10 µM
72 hours
UNC0379 significantly inhibited the proliferation, migration, and invasion of Huh-7 cells.
Sci Rep. 2020 Mar 11;10(1):4490.
SMMC-7721 cells
5 µM and 10 µM
72 hours
UNC0379 significantly inhibited the proliferation, migration, and invasion of SMMC-7721 cells.
Sci Rep. 2020 Mar 11;10(1):4490.
RDES cells
2 µM
72 hours
Evaluate the cytotoxicity of UNC0379 on RDES cells, results showed RDES cells were sensitive to UNC0379.
Cell Death Dis. 2024 Jul 10;15(7):494.
A673 cells
2 µM
72 hours
Evaluate the cytotoxicity of UNC0379 on A673 cells, results showed A673 cells were sensitive to UNC0379.
Cell Death Dis. 2024 Jul 10;15(7):494.
UNC0379 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
C57BL/6J mice
BLM-induced lung fibrosis model
Intratracheal administration
1 mg/kg/day
Administered at 7, 8, and 9 dpi
UNC0379 significantly ameliorated BLM-induced lung fibrosis without affecting inflammatory responses.
Front Mol Biosci. 2020 Aug 5;7:192.
Nude mice
Neuroblastoma xenograft model
Ex-vivo treatment followed by subcutaneous implantation
2 μM
Single treatment for 24 hours followed by implantation and tumor growth monitoring
UNC0379 treatment significantly inhibited tumor growth of SY5Y and NGP neuroblastoma cells in vivo and significantly prolonged murine survival.
Cancer Cell. 2017 Jan 9;31(1):50-63.
Nude mice
A673 cell xenograft model
30 mg/kg/day
Once daily for 14 days
Evaluate the anti-tumor effect of UNC0379 in vivo, results showed UNC0379 significantly reduced tumor volume and weight.
Cell Death Dis. 2024 Jul 10;15(7):494.
NSG mice
Subcutaneous and intrasplenic injection models
Intraperitoneal injection
5 mg/kg
3 times per week for 3 weeks
Evaluating the effect of UNC0379 on tumor growth and metastasis in vivo, results showed that UNC0379 alone or in combination with Tocilizumab delayed disease progression and prolonged survival.
Mol Cancer. 2025 Mar 31;24(1):102.
C57BL/6J mice
Cisplatin-induced acute kidney injury (AKI) model
Intraperitoneal injection
5 mg/kg
Once daily for three consecutive days
To investigate the effect of UNC0379 on cisplatin-induced AKI, results showed that UNC0379 improved renal function, attenuated renal tubular damage, and restored PTEN expression.
Cell Death Dis. 2025 Mar 31;16(1):226.
BALB/c nude mice
Subcutaneous tumor model
Intraperitoneal and subcutaneous injection
5 mg/kg
Twice weekly cisplatin and thrice weekly UNC0379 for 18 days
UNC0379 significantly reduced tumor size and weight, enhancing the therapeutic effect of cisplatin.
Cell Biosci. 2023 Jun 12;13(1):107.
CD1 mice
Glioblastoma xenograft model
5 μM UNC0379 + 400 nM adavosertib
From day 8 to day 21
UNC0379 and adavosertib combination significantly inhibited glioblastoma growth
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