AI-10-49Inhibitor of CBFβ –SMMHC and RUNX1 interaction CAS# 1256094-72-0 |
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| Cas No. | 1256094-72-0 | SDF | Download SDF |
| PubChem ID | 49806644 | Appearance | Powder |
| Formula | C30H22F6N6O5 | M.Wt | 660.52 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 34 mg/mL (51.47 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 6-(trifluoromethoxy)-2-[5-[2-[2-[6-[6-(trifluoromethoxy)-1H-benzimidazol-2-yl]pyridin-3-yl]oxyethoxy]ethoxy]pyridin-2-yl]-1H-benzimidazole | ||
| SMILES | C1=CC2=C(C=C1OC(F)(F)F)NC(=N2)C3=NC=C(C=C3)OCCOCCOC4=CN=C(C=C4)C5=NC6=C(N5)C=C(C=C6)OC(F)(F)F | ||
| Standard InChIKey | WJBSSBFGPKTMQQ-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C30H22F6N6O5/c31-29(32,33)46-17-1-5-21-25(13-17)41-27(39-21)23-7-3-19(15-37-23)44-11-9-43-10-12-45-20-4-8-24(38-16-20)28-40-22-6-2-18(14-26(22)42-28)47-30(34,35)36/h1-8,13-16H,9-12H2,(H,39,41)(H,40,42) | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | AI-10-49 is a protein-protein interaction inhibitor that selectively binds to CBFβ-SMMHC and disrupts its binding to RUNX1 with a FRET IC50 of 0.26 uM.
IC50 value: 0.26 uM [1]
Target: CBFβ-SMMHC/RUNX1 interaction inhibitor
AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics,
and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers. References: | |||||
| Cell experiment [1]: | |
| Cell lines | ME-1 (human leukemia cell lines) |
| Preparation method | Limited solubility. General tips for obtaining a higher concentration: Please warm the tube at 37 ℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
| Reacting condition | 6 h |
| Applications | After 6 hours of treatment, AI-10-49 effectively dissociates RUNX1 from CBFb-SMMHC with 90% dissociation, by contrast, it has a mild effect on CBFb-RUNX1 association. The ChIP assays indicates that AI-10-49 treatment on ME-1 cells for 6 hours increases RUNX1 occupancy 8-, 2.2-, and 8-fold at the RUNX3, CSF1R, and CEBPA promoters. |
| Animal experiment [1]: | |
| Animal models | Transplanted mice with Cbfb+/MYH11:Ras+/G12D leukemic cells |
| Dosage form | 200 mg/kg; 10 days |
| Application | Mice treated with AI-10-49 survives markedly longer (median latency = 61 days) and transient AI-10-49 treatment also reduces leukemia spreading in vivo. |
| Other notes | Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
| References: 1. Illendula A, Pulikkan JA, Zong H et.al A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science. 2015 Feb 13;347(6223):779-84. | |
AI-10-49 Dilution Calculator
AI-10-49 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.514 mL | 7.5698 mL | 15.1396 mL | 30.2792 mL | 37.849 mL |
| 5 mM | 0.3028 mL | 1.514 mL | 3.0279 mL | 6.0558 mL | 7.5698 mL |
| 10 mM | 0.1514 mL | 0.757 mL | 1.514 mL | 3.0279 mL | 3.7849 mL |
| 50 mM | 0.0303 mL | 0.1514 mL | 0.3028 mL | 0.6056 mL | 0.757 mL |
| 100 mM | 0.0151 mL | 0.0757 mL | 0.1514 mL | 0.3028 mL | 0.3785 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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AI-10-49 is a selective inhibitor of CBFβ –SMMHC and RUNX1 interaction with a FRET IC50 value of 260nM.
AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient with AI-10-49 triggers selective cell death. Direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers. The stability of RUNX1, CBFb, and CBFb-SMMHC was not affected by AI-10-49 [1].
In 11 human leukemia cell lines, ME-1 cells were the only cell line highly sensitive to AI-10-49. In ME-1 cell, AI-10-49 has enhanced inhibitory activity on growth (IC50 = 0.6 mM) compared with the parent protonated bivalent compound AI-4-83 (IC50 of ~3 mM). In normal human bone marrow cells, AI-10-49 showed negligible activity (IC50 > 25 mM), which indicated a robust potential therapeutic window. In chromatin-immunoprecipitation (ChIP) assays, treatment of ME-1 cells for 6 hours with AI-10-49 increased RUNX1 occupancy 8-, 2.2-, and 8-fold at the RUNX3, CSF1R, and CEBPA promoters, respectively.
After treatment with AI-10-49 to leukemia mice significantly prolonged their lives, and after 7 days of administration of AI-10-49, we observe no evidence of toxicity [1].
Reference:
1.Illendula A, Pulikkan JA, Zong H et al. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science. 2015 Feb 13;347(6223):779-784.
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Molecular Basis and Targeted Inhibition of CBFbeta-SMMHC Acute Myeloid Leukemia.[Pubmed:28299661]
Adv Exp Med Biol. 2017;962:229-244.
Acute myeloid leukemia (AML) is characterized by recurrent chromosomal rearrangements that encode for fusion proteins which drive leukemia initiation and maintenance. The inv(16) (p13q22) rearrangement is a founding mutation and the associated CBFbeta-SMMHC fusion protein is essential for the survival of inv(16) AML cells. This Chapter will discuss our understanding of the function of this fusion protein in disrupting hematopoietic homeostasis and creating pre-leukemic blasts, in its cooperation with other co-occurring mutations during leukemia initiation, and in leukemia maintenance. In addition, this chapter will discuss the current approaches used for the treatment of inv(16) AML and the recent development of AI-10-49, a selective targeted inhibitor of CBFbeta-SMMHC/RUNX1 binding, the first candidate targeted therapy for inv(16) AML.
Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFbeta-SMMHC delays leukemia in mice.[Pubmed:25678665]
Science. 2015 Feb 13;347(6223):779-84.
Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFbeta-SMMHC (core binding factor beta and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFbeta for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBFbeta-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFbeta-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers.
