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Purity: ≥98%
BETd-246 is a novel, potent and second-generation BET bromodomain (BRD) degrader which exhibits superior selectivity, potency and antitumor activity. Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In human TNBC cells, BETd-246 induced degradation of BET proteins at low nanomolar concentrations within 1 hour of exposure, resulting in robust growth inhibition and apoptosis. BETd-246 was more potent and effective in TNBC cells than its parental BET inhibitor compound BETi-211. RNA-seq analysis revealed predominant downregulation of a large number of genes involved in proliferation and apoptosis in cells treated with BETd-246, as compared with BETi-211 treatment that upregulated and downregulated a similar number of genes. Functional investigations identified the MCL1 gene as a critical downstream effector for BET degraders, which synergized with small-molecule inhibitors of BCL-xL in triggering apoptosis. In multiple murine xenograft models of human breast cancer, BETd-246 and a further optimized analogue BETd-260 effectively depleted BET proteins in tumors and exhibited strong antitumor activities at well-tolerated dosing schedules. Overall, these findings show that targeting BET proteins for degradation represents an effective therapeutic strategy for TNBC treatment.
| ln Vitro |
In test TNBC cell lines, BETd-246 treatment (0-100 nM, 1-3 hours) causes dose-dependent BRD2, BRD3, and BRD4 depletion (30-100 nM for 1 hour or 10-30 nM for 3 hours of incubation). In the MDA-MB-468 cell line, BETd-246 (100 nM, 24/48 hours) has potent growth inhibitory and apoptosis-inducing properties. In every TNBC cell line tested, BETd-246 causes the MCL1 protein to be rapidly and time-dependently downregulated. More apoptosis was triggered by BETd-246 than by BETi-211. In TNBC cell lines, BETd-246 (100 nM, 24 h) significantly promotes cell cycle arrest and apoptosis [1].
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| ln Vivo |
The administration of BETd-246 (5 mg/kg, intravenous injection, three times per week for three weeks) substantially reduced the growth of WHIM24 tumors, exhibiting anti-tumor efficacy comparable to that of BETi-211 at higher doses and more frequent administration. Partial tumor regression was induced after therapy at a dose of 10 mg/kg without any apparent side effects. BETd-246 drug exposure in xenograft tumor tissue was very low in the MDA-M-231 and MDA-MB-468 models [1].
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| Cell Assay |
Cell proliferation analysis [1]
Cell Types: MDA-MB-468 Cell Tested Concentrations: 100 nM Incubation Duration: 24 or 48 hrs (hours) Experimental Results: demonstrated strong growth inhibition and apoptosis-inducing activity in TNBC cell lines. Cell cycle analysis[1] Cell Types: Human TNBC Cell Tested Concentrations: 100 nM Incubation Duration: 24 hrs (hours) Experimental Results: Induced significant cell cycle arrest and apoptosis in TNBC cell line. Western Blot Analysis[1] Cell Types: Human TNBC Cell Tested Concentrations: 0-100 nM Incubation Duration: 1-3 hrs (hours) Experimental Results: Caused dose-dependent depletion of BRD2, BRD3 and BRD4. |
| Animal Protocol |
Animal/Disease Models: The “Washington Human Mouse (WHIM)” (PDX) model was developed from patients with refractory breast cancer (ESRE380Q, PR- and HER2-) [1].
Doses: 5, 10 mg/kg Route of Administration: intravenously (iv) (iv)(iv), 3 times a week for 3 weeks. Experimental Results: Effectively inhibited WHIM24 tumor growth. |
| References |
[1]. Bai L, et al. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer. Cancer Res. 2017 May 1;77(9):2476-2487.
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| Molecular Formula |
C48H55N11O10
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| Molecular Weight |
946.018010377884
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| CAS # |
2140289-17-2
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| SMILES |
O=C(C1=NC(NC2=CC(C3CC3)=NN2CC)=C4C(NC5=C4C=C(OC)C(C6=C(C)ON=C6C)=C5)=N1) NCCCOCCOCCOCCCNC7=CC=CC(C(N8C(CC9)C(NC9=O)=O)=O)=C7C8=O
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| Synonyms |
BETd-246; BETd246; BETd 246
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture. |
| 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 : ~200 mg/mL (~211.41 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (5.29 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0571 mL | 5.2853 mL | 10.5706 mL | |
| 5 mM | 0.2114 mL | 1.0571 mL | 2.1141 mL | |
| 10 mM | 0.1057 mL | 0.5285 mL | 1.0571 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.
 BETd-246 is a potent and highly selective degrader of BET proteins.Cancer Res.2017 May 1;77(9):2476-2487. |
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 BETd-246 displays potent antiproliferative and apoptosis induction activities in TNBC cell lines.Cancer Res.2017 May 1;77(9):2476-2487. |
 BET inhibitor and degrader elicit extensive but different transcriptome changes in TNBC cells.Cancer Res.2017 May 1;77(9):2476-2487. |
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