BETd-246
目录号 : GC65506
BETd-246 是第二代、基于 PROTAC 技术的、 BET溴端结构域 (BRD) 的抑制剂，由Cereblon配体和BET配体相连，具有良好的选择性、有效性和抗肿瘤活性。
Cas No.:2140289-17-2
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
BETd-246 is a second-generation and PROTAC-based BET bromodomain (BRD) inhibitor connected by ligands for Cereblon and BET, exhibiting superior selectivity, potency and antitumor activity[1].
BETd-246 treatment (0-100 nM, 1-3 h) causes a dose-dependent depletion of BRD2, BRD3 and BRD4 in representative TNBC cell lines with 30-100 nM for 1 h or with 10-30 nM for 3 h incubation. BETd-246 (100 nM, 24/48 hours) displays strong growth inhibition and apoptosis induction activity in MDA-MB-468 cell lines. BETd-246 induces a rapid and time-dependent downregulation of MCL1 protein in all the TNBC cell lines evaluated. BETd-246 induces much stronger apoptosis than BETi-211.BETd-246 (100 nM, 24 hours) induces pronounced cell cycle arrest and apoptosis in TNBC cell lines[1].
BETd-246 (5 mg/kg, IV, 3 times per week for 3 weeks) treatment effectively inhibits WHIM24 tumor growth, similar to the antitumor activity of BETi-211 with higher dosage and more frequently administration. The treatment of 10 mg/kg induces partial tumor regression during treatment without apparent toxicity. BETd-246 has very limited drug exposure in the xenograft tumor tissue in MDA-M-231and MDA-MB-468 models[1].
[1]. Bai L, et al. Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer. Cancer Res. 2017 May 1;77(9):2476-2487.
| Cas No. | 2140289-17-2 | SDF | Download SDF |
| 分子式 | C48H55N11O10 | 分子量 | 946.02 |
| 溶解度 | DMSO : 200 mg/mL (211.41 mM; Need ultrasonic) | 储存条件 | Store at -20°C, stored under nitrogen |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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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 |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Targeted Degradation of BET Proteins in Triple-Negative Breast Cancer
Cancer Res 2017 May 1;77(9):2476-2487.PMID:28209615DOI:10.1158/0008-5472.CAN-16-2622.
Triple-negative breast cancers (TNBC) remain clinically challenging with a lack of options for targeted therapy. In this study, we report the development of a second-generation BET protein degrader, BETd-246, which exhibits superior selectivity, potency, and antitumor activity. 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, our findings show that targeting BET proteins for degradation represents an effective therapeutic strategy for TNBC treatment. Cancer Res; 77(9); 2476-87. ©2017 AACR.
Characterizing the Therapeutic Potential of a Potent BET Degrader in Merkel Cell Carcinoma
Neoplasia 2019 Mar;21(3):322-330.PMID:30797188DOI:10.1016/j.neo.2019.01.003.
Studies on the efficacy of small molecule inhibitors in Merkel cell carcinoma (MCC) have been limited and largely inconclusive. In this study, we investigated the therapeutic potential of a potent BET degrader, BETd-246, in the treatment of MCC. We found that MCC cell lines were significantly more sensitive to BETd-246 than to BET inhibitor treatment. Therapeutic targeting of BET proteins resulted in a loss of "MCC signature" genes but not MYC expression as previously described irrespective of Merkel cell polyomavirus (MCPyV) status. In MCPyV+ MCC cells, BETd-246 alone suppressed downstream targets in the MCPyV-LT Ag axis. We also found enrichment of HOX and cell cycle genes in MCPyV- MCC cell lines that were intrinsically resistant to BETd-246. Our findings uncover a requirement for BET proteins in maintaining MCC lineage identity and point to the potential utility of BET degraders for treating MCC.