Synonym
MYCi975; MYCi975; MYCi975; NUCC-0200975; NUCC0200975; NUCC 0200975;
IUPAC/Chemical Name
4'-chloro-6-((4-chlorobenzyl)oxy)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-ol
InChi Key
VSDFDVBYONIJLD-UHFFFAOYSA-N
InChi Code
InChI=1S/C25H16Cl2F6N2O2/c1-35-19(11-21(34-35)25(31,32)33)16-7-9-20(37-12-13-2-5-15(26)6-3-13)22(23(16)36)14-4-8-18(27)17(10-14)24(28,29)30/h2-11,36H,12H2,1H3
SMILES Code
OC1=C(C2=CC(C(F)(F)F)=NN2C)C=CC(OCC3=CC=C(Cl)C=C3)=C1C4=CC=C(Cl)C(C(F)(F)F)=C4
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO
Shelf Life
>3 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
More Info
Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents.
Biological target:
MYCi975 (NUCC-0200975) is a potent, selective and orally active inhibitor of MYC that disrupts MYC/MAX interaction, promotes MYC T58 phosphorylation and MYC degradation, and impairs MYC driven gene expression.
In vitro activity:
MYCi975 (975) inhibited cell viability in a MYC-dependent manner (Figure 7A, S8A and S8B) and selectively suppressed E-box-luciferase activity (Figure 7B). To assess the molecular pathways modulated by MYCi treatment in an unbiased manner, RNA-seq experiments were performed using P493–6 and PC3 cells. The ability to repress MYC with tetracycline treatment in the P493–6 model allowed us to directly compare empirical MYC targets in these cells after turning MYC “off” to the genes regulated by 975 treatment. The results, shown in Figure 7C, indicate that 975 affected the expression of 3647 genes, the majority (69%) of which are MYC responsive. Among the 975-regulated genes that did not respond to MYC (and may therefore represent off-target effects), the top altered pathways were related to small molecule compound metabolism process, consistent with a general cellular response to exposure to organic small molecule (Figure 7D). Next, the effects of 975 were compared to those of 361 by RNA-seq in PC3 cells. 975 affected the expression of a smaller number of genes (n = 3095) compared to 361 (n = 5033), of which 66.4% were common between the two compounds (Figure 7E). GO biological process analysis of the common genes showed that cell cycle and DNA replication were among the top down regulated pathways, while pathways related to cell death, response to organic compound and ER stress were upregulated (Table S3). GSEA analysis of genes uniquely regulated by 361 (n = 2978) showed suppression of several sets that all share common leading edge genes encoding HIST1H proteins and the TCA cycle/respiratory electron transport (Table S4). However, no gene sets were significantly enriched in GSEA analysis of genes uniquely regulated by 975 in PC3 cells. These findings may partly explain the improved tolerability of 975 compared to 361 as will be shown below.
Reference: Cancer Cell. 2019 Nov 11;36(5):483-497.e15. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31679823/
In vivo activity:
975 exhibited excellent pharmacokinetic profiles following p.o., i.p. or i.v. administration (Figure S8C and S8D). The half-lives observed were 7 hr and 12 hr when dosed at 100 mg/kg and 250 mg/kg p.o. respectively. The Cmax values attained were 41533 ng/ml (74 μM) and 54000 ng/ml (96 μM) respectively. 975 significantly inhibited tumor growth (Figures 8A) and increased survival (Figures 8B) in the MycCaP allograft model with animals tolerating a 100 mg/kg/day i.p. dosing for 14 days. Analysis of tumor tissue showed increased pT58 and PD-L1 levels (Figure 8C) and enhanced tumor infiltration of CD3+ T cells (Figure 8D), B220+ B Cells (Figure 8E), and NKp46+ NK cells (Figure 8F) after 975 treatment. Therefore, the effect of combining 975 with anti-PD1 treatment was examined. 975 alone dosed at 100 mg/kg/day, 2 days on/2 days off slowed tumor growth, while the combination treatment with anti-PD1 (100 μg/day, on alternating 2 days on/2 days off) resulted in a synergistic suppression of tumor growth (Figure 8G and S8E). Similar to 361, 975 treatment inhibited MycCaP tumors grown in immunocompetent FVB mice more strongly than in immunodeficient NSG mice (Figure 8H), indicating that full anti-tumor efficacy of 975 is also dependent on an intact immune system. Treatment of Lewis Lung Carcinoma (LLC1)-bearing mice with 975 (100 mg/kg/day) inhibited tumor growth with no changes in body weight (Figure 8I and S8F). NSG mice bearing MV-411 AML xenografts were treated with 975 (50 mg/kg/day) or Ara-C (20 mg/kg/day) 5 days a week. In this model, the lower dose of 975 and the immunodeficient host background may explain reduced efficacy as a single agent. 975 synergized with Ara-C with no obvious impact on mouse body weight (Figure 8J and S8G).
Reference: Cancer Cell. 2019 Nov 11;36(5):483-497.e15. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/31679823/
|
Solvent |
mg/mL |
mM |
| Solubility |
| Soluble in DMSO |
56.0 |
99.80 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
561.31
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I, Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell. 2019 Nov 11;36(5):483-497.e15. doi: 10.1016/j.ccell.2019.10.001. Epub 2019 Oct 31. PMID: 31679823; PMCID: PMC6939458.
In vivo protocol:
1. Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I, Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA. Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell. 2019 Nov 11;36(5):483-497.e15. doi: 10.1016/j.ccell.2019.10.001. Epub 2019 Oct 31. PMID: 31679823; PMCID: PMC6939458.
2. Truica MI, Burns MC, Han H, Abdulkadir SA. Turning Up the Heat on MYC: Progress in Small-Molecule Inhibitors. Cancer Res. 2021 Jan 15;81(2):248-253. doi: 10.1158/0008-5472.CAN-20-2959. Epub 2020 Oct 21. PMID: 33087323; PMCID: PMC7855142.
1: Han H, Jain AD, Truica MI, Izquierdo-Ferrer J, Anker JF, Lysy B, Sagar V, Luan
Y, Chalmers ZR, Unno K, Mok H, Vatapalli R, Yoo YA, Rodriguez Y, Kandela I,
Parker JB, Chakravarti D, Mishra RK, Schiltz GE, Abdulkadir SA. Small-Molecule
MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy. Cancer Cell. 2019
Nov 11;36(5):483-497.e15. doi: 10.1016/j.ccell.2019.10.001. Epub 2019 Oct 31.
PubMed PMID: 31679823; PubMed Central PMCID: PMC6939458.
