MYC proteins, including MYC, MYCL, and MYCN, play critical roles in tumorigenesis and therapeutic resistance. MYCi975 is an inhibitor of MYC that binds to intracellular MYC with a KD of 2.5 μM. Treatment of PC3 cells with MYCi975 (8 μM) enhanced MYC degradation and phosphorylation on T58. MYCi975 (6 μM) directly increased GSK3β-mediated MYC pT58 in the in vitro kinase assay. In prostate cancer cells and PC12 cells, MYCi975 inhibited cell viability in an MYC-dependent manner and selectively suppressed E-box luciferase activity. MYCi975 (6 μM; 24 h) affected the expression of 3,647 genes, most (69%) of which were MYC responsive. In vivo, MYCi975 significantly inhibited tumor growth and increased survival in the MycCaP allograft model with animals tolerating a 100 mg/kg/day i.p. dosing for 14 days. It increased pT58 and PD-L1 levels and enhanced tumor infiltration of CD3+ T cells, B220+ B Cells, and NKp46+ NK cells. Moreover, treatment of Lewis lung carcinoma (LLC1)-bearing mice with MYCi975 (100 mg/kg/day) inhibited tumor growth with no changes in body weight[2].
作用机制
MYCi975 binds to amino acids 353–439 of the MYC protein[2].
MYCi975 细胞实验
Cell Line
Concentration
Treated Time
Description
References
P493-6 cells
6 μM
24 hours
To assess the effect of MYCi975 on MYC-dependent gene expression, results showed that MYCi975 significantly suppressed the expression of MYC target genes.
Cancer Cell. 2019 Nov 11;36(5):483-497.e15.
PC3 cells
6 μM
1 hour
To assess the effect of MYCi975 on MYC/MAX interaction, results showed that MYCi975 significantly disrupted the formation of MYC/MAX complex.
Cancer Cell. 2019 Nov 11;36(5):483-497.e15.
HN12 cells
5 μM
48 hours
To evaluate the effect of MYCi975 on cellular glutamine consumption, results showed that MYCi975 significantly inhibited glutamine consumption
Cancer Res. 2024 Oct 1;84(19):3223-3234.
HN6 cells
5 μM
48 hours
To evaluate the effect of MYCi975 on cellular glutamine consumption, results showed that MYCi975 significantly inhibited glutamine consumption
Cancer Res. 2024 Oct 1;84(19):3223-3234.
MCF7 breast cancer cells
10 μM
48 hours
MYCi975 treatment reduced FOXA1 occupancy at co-occurring ERα binding sites.
Sci Adv. 2022 Apr 29;8(17):eabh3635.
P493-6 lymphoma cells
6 μM
24 hours
MYCi975 treatment affected gene expression related to DNA metabolic process, DNA replication, and cell cycle pathways.
Sci Adv. 2022 Apr 29;8(17):eabh3635.
PC3 prostate cancer cells
8 μM
24 hours
MYCi975 treatment affected gene expression related to DNA metabolic process, DNA replication, and cell cycle pathways.
Sci Adv. 2022 Apr 29;8(17):eabh3635.
22Rv1 prostate cancer cells
10 μM
1, 4, 8, 24, 48 hours
Evaluated the kinetics of MYC protein down-regulation, MYCi975 induced MYC protein down-regulation in a time-dependent manner, achieving approximately >90% decrease in MYC protein levels by 48 hours.
Sci Adv. 2022 Apr 29;8(17):eabh3635.
H929 cells
5 μM
48 hours
Evaluate the effect of MYCi975 on H929 cells, showing MYCi975 enhanced T cell-mediated killing of H929 cells
Clin Cancer Res. 2024 Jul 15;30(14):3023-3035.
Primary MM cells
1 μM
48 hours
Evaluate the sensitivity of primary MM cells to MYCi975, showing 89% of samples were sensitive to MYCi975 with MYC protein degradation
Clin Cancer Res. 2024 Jul 15;30(14):3023-3035.
MYCi975 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MycCaP allograft model
I.p.
100 mg/kg/day
Once daily for 14 days
To assess the inhibitory effect of MYCi975 on tumor growth, results showed that MYCi975 significantly inhibited tumor growth and increased tumor immune cell infiltration.
Cancer Cell. 2019 Nov 11;36(5):483-497.e15.
Nude mice
22Rv1 xenograft model
Oral
100 mg/kg BID
5 days a week for 3 weeks
MYCi975 (100 mg/kg BID) led to a significant inhibition of tumor growth without any adverse effect on mouse body weight.
Sci Adv. 2022 Apr 29;8(17):eabh3635.
NSG mice
Orthotopic buccal mucosal tumor model
Intraperitoneal injection
100 mg/kg
Once daily for 15 days
To evaluate the antitumor efficacy of MYCi975 alone or in combination with CB-839, results showed that the combination therapy significantly suppressed tumor growth and lymph node metastasis
Cancer Res. 2024 Oct 1;84(19):3223-3234.
NOD/SCID mice
HNSCC PDX model
Intraperitoneal injection
100 mg/kg
Every 2 days for 6 weeks
Investigate the effect of MYCi975 on HNSCC PDX model, including inhibition of tumor growth and overcoming cisplatin resistance.
Theranostics. 2024 Jan 1;14(2):622-639
BALB/c-nude female mice
Cell line-derived xenograft model
Subcutaneous injection
100 mg/kg
Every 2 days for 4 weeks
MYCi975 inhibited HNSCC growth and promoted CD8+ T cell infiltration.
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