10058-F4 inhibits the growth of leukemic cells and the dimerization of Myc and Max. It induces cell-cycle arrest and apoptosis of AML cells, primarily arresting them at the G0/G1 phase. Moreover, 10058-F4 downregulates c-Myc expression and upregulates CDK inhibitors, such as p21 and p27. Additionally, it induces apoptosis through the activation of the mitochondrial pathway, characterized by the downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 promotes myeloid differentiation, possibly via the activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation are also evident in primary AML cells [1]. 10058-F4 reduces c-Myc protein levels and inhibits proliferation of HepG2 cells, likely by upregulating the cyclin-dependent kinase (cdk) inhibitor, p21WAF1, and decreasing intracellular levels of alpha-fetoprotein (AFP). Treatment with 10058-F4 also suppresses human telomerase reverse transcriptase (hTERT) at the transcriptional level. Moreover, besides inhibiting the proliferation of HepG2 cells, 10058-F4 enhances sensitivity to conventional chemotherapeutic agents, including doxorubicin, 5-fluorouracil (5-FU), and cisplatin [2].
体内研究
Following a single intravenous dose, peak plasma concentrations of 10058-F4 reach approximately 300 μM at 5 minutes and decline below the detection limit by 360 minutes. Plasma concentration versus time data are best fitted by a two-compartment, open, linear model. The highest concentrations of 10058-F4 are observed in fat, lung, liver, and kidney tissues. Tumor concentrations of 10058-F4 peak at levels at least tenfold lower than peak plasma concentrations. Eight metabolites of 10058-F4 are identified in plasma, liver, and kidney. The terminal half-life of 10058-F4 is approximately 1 hour, and the volume of distribution exceeds 200 mL/kg. No significant inhibition of tumor growth is observed after intravenous treatment of mice with either 20 or 30 mg/kg 10058-F4 [3].
体外研究
10058-F4 inhibits the growth of leukemic cells and the dimerization of Myc and Max. It induces cell-cycle arrest and apoptosis of AML cells, primarily arresting them at the G0/G1 phase. Moreover, 10058-F4 downregulates c-Myc expression and upregulates CDK inhibitors, such as p21 and p27. Additionally, it induces apoptosis through the activation of the mitochondrial pathway, characterized by the downregulation of Bcl-2, upregulation of Bax, release of cytoplasmic cytochrome C, and cleavage of caspase 3, 7, and 9. Furthermore, 10058-F4 promotes myeloid differentiation, possibly via the activation of multiple transcription factors. Similarly, 10058-F4-induced apoptosis and differentiation are also evident in primary AML cells [1].
10058-F4 reduces c-Myc protein levels and inhibits proliferation of HepG2 cells, likely by upregulating the cyclin-dependent kinase (cdk) inhibitor, p21WAF1, and decreasing intracellular levels of alpha-fetoprotein (AFP). Treatment with 10058-F4 also suppresses human telomerase reverse transcriptase (hTERT) at the transcriptional level. Moreover, besides inhibiting the proliferation of HepG2 cells, 10058-F4 enhances sensitivity to conventional chemotherapeutic agents, including doxorubicin, 5-fluorouracil (5-FU), and cisplatin [2].
10058-F4 细胞实验
Cell Line
Concentration
Treated Time
Description
References
TMR cells
10 μM
Reduced expression of HOXB7, HER2, and ER target genes
Cancer Discov. 2015 Sep;5(9):944-59.
BT474 cells
1, 5, 10, 50 μM
48 h
Combined with trastuzumab, significantly reduced cell viability
Cancer Discov. 2015 Sep;5(9):944-59.
H1299 cells
10 µM
24 h
Inhibited MYC expression and increased p21 protein levels
Nat Commun. 2021 Aug 13;12(1):4919.
human mammary epithelial cells (hMECs)
10μM
To investigate the effect of MYC inhibitor 10058-F4 on miR-18a expression, results showed that 10058-F4 significantly reduced miR-18a expression in hMECs cultured on stiff substrates.
Nat Med. 2014 Apr;20(4):360-7.
Jurkat cells
5 nM
12 h
Inhibited c-Myc expression, reduced GLS1 and GLUD expression, impaired T cell activation and proliferation
Adv Sci (Weinh). 2023 Apr;10(12):e2201164.
intestinal organoids
20 μM or 40 μM
24 h
increased the secretion of total GLP-1 and active GLP-1 in response to glucose, along with elevated Gcg mRNA levels
Nat Metab. 2021 Jul;3(7):923-939.
intestinal organoids
40 μM
48 h
reduced ceramide production and secretion
Nat Metab. 2021 Jul;3(7):923-939.
DU145
100 nM
48 h
To evaluate the effect of MYC inhibitor 10058-F4 on the radiosensitivity of DU145 cells, results showed that 10058-F4 significantly increased the radiosensitivity of DU145 cells.
Theranostics. 2021 Jun 26;11(16):7844-7868.
LNCaP
100 nM
48 h
To evaluate the effect of MYC inhibitor 10058-F4 on the radiosensitivity of LNCaP cells, results showed that 10058-F4 had a minor effect on the radiosensitivity of LNCaP cells.
Theranostics. 2021 Jun 26;11(16):7844-7868.
intestinal organoids
20 μM or 40 μM
24 h or 48 h
Treatment with 10058-F4 increased Gcg mRNA levels in intestinal organoids and promoted the secretion of total GLP-1 and active GLP-1.
Nat Metab. 2021 Jul;3(7):923-939.
10058-F4 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NSG mice
BT474 cell xenograft model
Intraperitoneal injection
30 mg/kg
Daily, for the duration of the treatment
Combined with trastuzumab, significantly inhibited tumor growth
Cancer Discov. 2015 Sep;5(9):944-59.
Nude mice
MDA-MB-231/ADR xenograft model
Intraperitoneal injection
20 mg/kg
Every 3 days for 3 weeks
The combination of 10058-F4 and DOX significantly slowed down the tumor growth rate in nude mice and reduced the tumor size and weight.
Cell Death Dis. 2022 Apr 12;13(4):338
Nile tilapia
Bacterial infection model
Intraperitoneal injection
10 mg/kg
Administered on day 1, 3, 5, and 6 post-infection
Inhibited c-Myc expression, reduced GLS1 and GLUD expression, impaired T cell proliferation and cytotoxicity, increased infection mortality
Adv Sci (Weinh). 2023 Apr;10(12):e2201164.
Mice
TPO-Cre/LSL-BrafV600E mice
Gastric gavage and intraperitoneal injection
30 mg/kg
Once daily for 2 weeks
To investigate the effect of 10058-F4 on PRC2 components and H3K27me3 levels in BrafV600E-induced thyroid cancer mouse model, the results showed that 10058-F4 significantly reduced tumor volume and weight, and decreased the levels of PRC2 components and H3K27me3
Theranostics. 2017 May 26;7(7):2092-2107
Mice
HFD-induced obesity and hepatic steatosis model
Oral
50 mg/kg
Daily for 8 weeks
Improved HFD-induced obesity, insulin resistance, hepatic steatosis and fibrosis, accompanied by increased GLP-1 and decreased ceramide levels in serum
Nat Metab. 2021 Jul;3(7):923-939.
Mice
High-fat diet-induced obesity and hepatic steatosis model
Oral
50 mg/kg
Daily for 8 weeks
10058-F4 treatment reduced and liver weight gain, improved insulin resistance, and reduced hepatic steatosis.
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