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Purity: =99.63%
MYCi975 (NUCC-0200975), an MYCi361 analog, is a novel, orally bioactive and potent MYC inhibitor (Kd = 3.2 μM) with potential anticancer activity. As an improved analog of MYCi361, MYCi975 showed better tolerability. MYCi975 phosphorylated MYC within cells, shattered MYC/MAX dimers, and reduced MYC-stimulated gene expression. Additionally, it increased threonine-58 MYC phosphorylation, which in turn increased MYC degradation mediated by proteasomes. MYCi975 was able to improve anti-PD1 immunotherapy and inhibit the growth of tumors.
| Targets |
MYC
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|---|---|
| ln Vitro |
MYCi975 localizes to the MYC protei's same region. The application of MYCi975 to cells increases T58 phosphorylation and MYC degradation. In the in vitro kinase test, MYCi975 also directly raises GSK3b-mediated MYC pT58.[1]
The initial lead, MYC inhibitor 361 (MYCi361), suppressed in vivo tumor growth in mice, increased tumor immune cell infiltration, upregulated PD-L1 on tumors, and sensitized tumors to anti-PD1 immunotherapy. However, 361 demonstrated a narrow therapeutic index. An improved analog, MYCi975 showed better tolerability. These findings suggest the potential of small-molecule MYC inhibitors as chemical probes and possible anti-cancer therapeutic agents[1]. |
| ln Vivo |
MYCi975 upregulates PD-L1 on tumors, enhances tumor immune cell infiltration, inhibits in vivo tumor growth in mice, and effectively sensitizes tumors to anti-PD1 immunotherapy.[1]
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| Enzyme Assay |
EMSA assay [1]
E-box containing dsDNA oligonucleotide with one strand labeled with hexachlorofluorescein for fluorescence visualization was synthesized by IDT, Inc. The sequence of the oligonucleotide is 5-CACCCGGTCACGTGGCCTACAC-3 as previously reported (Wang et al., 2007). The binding reaction buffer consists of 0.005% IGEPAL CA-630, 5% glycerol, 1 mM EDTA in 1xPBS. The concentration of MYC (residues 353–439), referred to as MYC in EMSA assay, MAX(S) and MAX(L) (as negative control) was 60 nM, and the Oligo was 20nM in the assay. All compounds were dissolved in DMSO at 20 or 40 mM and stored in −20 C°. To prepare the reaction mixture, compounds were further diluted into reaction buffer/DMSO 6:4 to make 10 times the final concentration; 2 μl of prepared compound was added into 18 μl of reaction buffer containing either MYC or MAX and incubated for 1 hr at room temperature. The oligo was added to MAX(S) reaction mix before incubation with compounds since MAX(S) does not bind to oligo by itself. The MYC/compound solution was finally mixed with MAX(S)/oligo/compound solution and the binding reaction allowed to proceed for 15 min before loading 20ul of sample to native gel prepared with 8% of acrylamide/bis-acrylamide (80:1), 10% glycerol in 0.5xTris-borate EDTA (TBE) buffer. The gel was run for 45 min at constant voltage (80 V), and scanned with Alexa Fluor 546 on a Bio-Rad FX molecular imager (Bio-Rad). Data were analyzed with Image J software. |
| Cell Assay |
PC3 cells are treated for 24 hours in triplicate with either 6 μM 361 or 8 μM 975, while P493-6 cells are treated for 24 hours with either 0.1 mg/ml Tetracycline or 6 μM 975. After that, cells are cleaned with PBS and the RNAeasy Plus mini kit is used to extract RNA.
Proliferation assay and NCI 60 panel screen[1] Cell viability was estimated using the MTS kit, CellTiter 96 AQueous One Solution or by counting viable cells. According to cell type and experimental setting, 1000 to 5000 cells/well were seeded in 96 well plates. For rat fibroblast cells, HO15.19 (1000/well) and TGR.1 (3000/well) were seeded in 48 well plates. After 2 to 7 days following the treatment, viable cells were counted or MTS reagent was added and absorption at 490 was measured using plate reader. NCI-60 human tumor cell lines screen for the compounds were performed by the Developmental Therapeutics Program of the National Cancer Institute. MYC expression levels of NCI-60 cell lines were analyzed using gene transcript level Z score analysis tool (https://discover.nci.nih.gov/cellminer/). |
| Animal Protocol |
6-8 weeks old FVB mice, prostate PDX model (TM00298), NSG mice, C57BL/6, CB17/Icr-Prkdcscid/IcrIcoCrl mice, CD-1
50 mg/kg, 100 mg/kg IP |
| References | |
| Additional Infomation |
Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation. [1]
MYC plays critical roles in tumorigenesis and is considered an attractive cancer therapeutic target. Small molecules that directly target MYC and are well tolerated in vivo represent invaluable anti-cancer therapeutic agents. Here, we aimed to investigate the therapeutic effect of MYC inhibitors in head and neck squamous cell carcinoma (HNSCC). The results showed that pharmacological and genetic inhibition of MYC inhibited HNSCC proliferation and migration. MYC inhibitor 975 (MYCi975), inhibited HNSCC growth in both cell line-derived xenograft and syngeneic murine models. MYC inhibition also induced tumor cell-intrinsic immune responses, and promoted CD8+ T cell infiltration. Mechanistically, MYC inhibition increased CD8+ T cell-recruiting chemokines by inducing the DNA damage related cGAS-STING pathway. High expression of MYC combined with a low level of infiltrated CD8+ T cell in HNSCC correlated with poor prognosis. These results suggested the potential of small-molecule MYC inhibitors as anti-cancer therapeutic agents in HNSCC.[3] |
| Molecular Formula |
C25H16CL2F6N2O2
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|---|---|
| Molecular Weight |
561.3032
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| Exact Mass |
560.05
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| Elemental Analysis |
C, 53.50; H, 2.87; Cl, 12.63; F, 20.31; N, 4.99; O, 5.70
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| CAS # |
2289691-01-4
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| Related CAS # |
2289691-01-4;
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| PubChem CID |
139600320
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| Appearance |
Solid powder
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| LogP |
7.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
37
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| Complexity |
752
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
VSDFDVBYONIJLD-UHFFFAOYSA-N
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| 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
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| Chemical Name |
3-[(4-chlorophenyl)methoxy]-2-[4-chloro-3-(trifluoromethyl)phenyl]-6-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenol
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| Synonyms |
MYCi975; MYCi975; MYCi975; NUCC-0200975; NUCC 0200975; MYCi975; 2289691-01-4; 4'-chloro-6-((4-chlorobenzyl)oxy)-3-(1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3'-(trifluoromethyl)-[1,1'-biphenyl]-2-ol; NUCC-0200975; 3-[(4-chlorophenyl)methoxy]-2-[4-chloro-3-(trifluoromethyl)phenyl]-6-[2-methyl-5-(trifluoromethyl)pyrazol-3-yl]phenol; SCHEMBL21786611; VSDFDVBYONIJLD-UHFFFAOYSA-N; NUCC0200975
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ~100 mg/mL (~178.2 mM)
Ethanol: ~60 mg/mL (~106.9 mM) |
|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7816 mL | 8.9079 mL | 17.8158 mL | |
| 5 mM | 0.3563 mL | 1.7816 mL | 3.5632 mL | |
| 10 mM | 0.1782 mL | 0.8908 mL | 1.7816 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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