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Purity: ≥98%
666-15 is a novel, cell-permeable, potent and selective inhibitor of CREB (cAMP-response element binding protein)-mediated gene transcription with IC50 of 81 nM. Recent studies have shown that nuclear transcription factor cyclic adenosine monophosphate response element binding protein (CREB) is overexpressed in many different types of cancers. Therefore, CREB has been pursued as a novel cancer therapeutic target. 666-15 potently inhibits cancer cell growth without harming normal cells. 666-15 has high anti-cancer activity both in vitro and in vivo. In an in vivo MDA-MB-468 xenograft model, 666-15 completely suppressed the tumor growth without overt toxicity. These results further support the potential of CREB as a valuable cancer drug target.
| ln Vitro |
The consequences of MSN overexpression, such as cell ischemia, weakening, soft agar colony capability, and production of CREB downstream genes, are significantly blocked by 666-15 (73 nM) when given for a 12-hour period. 666-15 Prevents MSN-induced CREB phosphorylation 666-15 (1 μM; wait two hours) efficiently prevents PE-induced CREB phosphorylation. 666-15 suppresses middle ER activation, including PE + ylation, and dramatically lowers the protein production of ANP and β-MHC [2]. The phosphorylation of IRE1 and the expression of GRP78, CHOP, and ATF6 in the siRNA + 666-15 group and PE + si-CTRP3 + 666-15 group [3]. Template growth is substantially inhibited by 666-15. In MDA-MB-231 and MDA-MB-468 cells, the GI50 of 666-15 was 73 and 46 nM, respectively. The majority of actions were observed in A549 and MCF-7 cells, with GI50 values of 0.47 and 0.31 μM, respectively. With an IC50 of 18.27 μM, 666-15 was also discovered to have a relatively poor CREB-CBP binding reaction. In live cells, 666-15 transcribes CREB transcriptional activity without the need for direct binding reactions to CBP or CREB. Nuclear trap-related protein 1 (Nurr1/NR4A2) transcript levels are one of the endogenous CREB target genes that are inhibited by 666-15, which also transcribes CREB [1].
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| ln Vivo |
Results: It has a good effect on the growth of breast cancer. inhibitory effect. 666-15 (10 mg/kg; intraperitoneal injection; once a week; 11 consecutive weeks) can have a good effect on cell proliferation when used alone, and the effect is better when combined with RP-56976 (DOC) [2]. Animal model: 1-month-old female nude mice, MDA-MB-231 or T47D cells [2]. Dosage: 10 mg/kg Administration method: IP; once a week; for 11 consecutive weeks.
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| Cell Assay |
Cell Proliferation Assay[2]
Cell Types: CTRL or MSN overexpression MDA-MB-231 Cell Tested Concentrations: 73 nM Incubation Duration: 12 hrs (hours) Experimental Results: Dramatically blocked cell proliferation caused by MSN overexpression. Western Blot Analysis [3] Cell Types: NRCMs Tested Concentrations: 1 μM Incubation Duration: 2 hrs (hours) (pretreatment) Experimental Results: Effectively inhibited PE-induced CREB phosphorylation. |
| Animal Protocol |
Animal/Disease Models: 1-month-old female nude mice, MDA-MB-231 or T47D cells [2]
Doses: 10 mg/kg Route of Administration: IP; once a week; for 11 consecutive weeks. Experimental Results: It has a good effect on the growth of breast cancer. inhibitory effect. |
| References |
[1]. Xie F, et al. Identification of a Potent Inhibitor of CREB-Mediated Gene Transcription with Efficacious in Vivo Anticancer Activity. J Med Chem. 2015 Jun 25;58(12):5075-87.
[2]. Qin Y, et al. Interfering MSN-NONO complex-activated CREB signaling serves as a therapeutic strategy for triple-negative breast cancer. Sci Adv. 2020 Feb 19;6(8):eaaw9960. [3]. Zhang B, et al. C1q-TNF-related protein-3 attenuates pressure overload-induced cardiac hypertrophy by suppressing the p38/CREB pathway and p38-induced ER stress. Cell Death Dis. 2019 Jul 8;10(7):520. |
| Molecular Formula |
C33H31CL2N3O5
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|---|---|
| Molecular Weight |
620.5223
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| CAS # |
1433286-70-4
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| SMILES |
O=C(C1=C(OCCCN)C=C2C=CC=CC2=C1)NCCOC3=C(C(NC4=CC=C(Cl)C=C4O)=O)C=C5C=CC=CC5=C3.[H]Cl
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| InChi Key |
LELLCPHHYHLWBH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C33H30ClN3O5.ClH/c34-25-10-11-28(29(38)20-25)37-33(40)27-17-22-7-2-4-9-24(22)19-31(27)42-15-13-36-32(39)26-16-21-6-1-3-8-23(21)18-30(26)41-14-5-12-35;/h1-4,6-11,16-20,38H,5,12-15,35H2,(H,36,39)(H,37,40);1H
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| Chemical Name |
3-(3-Aminopropoxy)-N-[2-[[3-[[(4-chloro-2-hydroxyphenyl)amino]carbonyl]-2-naphthalenyl]oxy]ethyl]-2-naphthalenecarboxamide hydrochloride
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| Synonyms |
66615; 666 15; 666-15; Compound 3i
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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 : ~125 mg/mL (~201.44 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.35 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (3.35 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.35 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6116 mL | 8.0578 mL | 16.1155 mL | |
| 5 mM | 0.3223 mL | 1.6116 mL | 3.2231 mL | |
| 10 mM | 0.1612 mL | 0.8058 mL | 1.6116 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.
 Conformation of the global energy minimum of3a(A),3j(B),3h(C), and3i(D).
Compound3idecreased endogenous CREB target gene expression.J Med Chem. 2015 Jun 25;58(12):5075-87. |
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Compound3isuppressed MDA-MB-468 tumor growth in vivo.
Compound3iselectively inhibited CREB-mediated gene transcription. HEK 293T cells were transfected with indicated combinations of plasmids.J Med Chem. 2015 Jun 25;58(12):5075-87. |
 Compound3iselectively inhibited tumor cell growth.
Synthesis of Compounds3e–g.J Med Chem. 2015 Jun 25;58(12):5075-87. |
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