MSC-4106
目录号 : GC65993
MSC-4106 是一种具有口服活性的 YAP/TAZ-TEAD 抑制剂。 MSC-4106 阻断 TEAD1 和 TEAD3 的 auto-palmitoylation，对 NCI-H226 异种移植瘤模型具有抑制作用。
Cas No.:2738542-58-8
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >99.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
MSC-4106 is an orally active and potent inhibitor of YAP/TAZ-TEAD. MSC-4106 inhibits TEAD1 or TEAD3 auto-palmitoylation and shows inhibitory effect on NCI-H226 tumor xenograft model[1].
MSC-4106 (10 μM, 24 h) inhibited SK-HEP-1 reporter and NCI-266 cell viability with IC50 values of 4 nM and 14 nM, respectively[1].
MSC-4106 (10 μM, 6 h) crystallizes in the P-site of TEAD1, and against TEAD1 or TEAD3 palmitoylation in TEAD-Overexpressing HEK293 Cells by 97.3% and 75.9%, respectively[1].
MSC-4106 (10 μM, 4 d) targets TEAD indicated by a reduction in viability of NCI-H226 cells[1].
Cell Viability Assay[1]
| Cell Line: | NCI-H226 (YAP dependent); SW620 YAP/TAZ KO (Yap-independent) cells |
| Concentration: | 0, 3, 6, 9, 12, 15, 18, 21, 24, 26, 30 μM |
| Incubation Time: | 96 hours |
| Result: | Showed inhibitory effect to NCI-H226 and general cytotoxic to SW620 (IC50 >30 μM). |
Immunofluorescence[1]
| Cell Line: | SK-HEP-1 |
| Concentration: | 0, 3, 6, 9, 12, 15, 18, 21, 24, 26, 30 μM |
| Incubation Time: | 24 hours |
| Result: | Inhibited YAP-TEAD interation. |
MSC-4106 (100 mg/kg/d; p.o.; 7 d) displays anti-tumor effect with controlled tumor volume and good tolerability with stable body weight in mice[1].
MSC-4106 (1, 5, 100 mg/kg/d; p.o.; 0-72 h) down-regulates Cyr61 (cysteine-rich angiogenic inducer 61) expression, the TEAD-regulated target gene, in tumor lysates at all time points at 100 mg/kg and 24 h at 5 mg/kg[1].
Pharmacokinetics (PK) profile in different species[1]
| Parameter | Mouse | Rat | Dog |
| Cl (l/h/kg) | 0.2 | 0.7 | 0.05 |
| PO t1/2 (h) | 45 | 40 | 3.6 |
| PO AUC (μg•h/mL) | 45 | 10 | 33 |
| Vss (L/kg) | 2 | 5 | 0.3 |
| F (%) | >90 | 80 | 18 |
| Animal Model: | NCI-H226 xenograft model in H2d Rag2 female mice (9-week-old)[1] |
| Dosage: | 5, 100 mg/kg |
| Administration: | Oral gavage; once daily; 32 days |
| Result: | Resulted tumor growth controlled with 5 mg/kg while regressed with 100 mg/kg dosing after 32 treatment days. |
| Cas No. | 2738542-58-8 | SDF | Download SDF |
| 分子式 | C18H12F3N3O2 | 分子量 | 359.3 |
| 溶解度 | DMSO : 250 mg/mL (695.80 mM; Need ultrasonic) | 储存条件 | Store at -20°C, away from moisture |
| 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 | 2.7832 mL | 13.9159 mL | 27.8319 mL |
| 5 mM | 0.5566 mL | 2.7832 mL | 5.5664 mL |
| 10 mM | 0.2783 mL | 1.3916 mL | 2.7832 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。
Optimization of TEAD P-Site Binding Fragment Hit into In Vivo Active Lead MSC-4106
J Med Chem 2022 Jul 14;65(13):9206-9229.PMID:35763499DOI:10.1021/acs.jmedchem.2c00403
The dysregulated Hippo pathway and, consequently, hyperactivity of the transcriptional YAP/TAZ-TEAD complexes is associated with diseases such as cancer. Prevention of YAP/TAZ-TEAD triggered gene transcription is an attractive strategy for therapeutic intervention. The deeply buried and conserved lipidation pocket (P-site) of the TEAD transcription factors is druggable. The discovery and optimization of a P-site binding fragment (1) are described. Utilizing structure-based design, enhancement in target potency was engineered into the hit, capitalizing on the established X-ray structure of TEAD1. The efforts culminated in the optimized in vivo tool MSC-4106, which exhibited desirable potency, mouse pharmacokinetic properties, and in vivo efficacy. In close correlation to compound exposure, the time- and dose-dependent downregulation of a proximal biomarker could be shown.