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。
| 生物活性 | MSC-4106 is an orally active and potent inhibitor ofYAP/TAZ-TEAD. MSC-4106 inhibitsTEAD1orTEAD3auto-palmitoylation and shows inhibitory effect on NCI-H226 tumor xenograft model[1]. |
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体外研究
(In Vitro) | MSC-4106 (10 μM, 24 h) inhibited SK-HEP-1 reporter and NCI-266 cell viability with IC50values 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. |
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体内研究
(In Vivo) | 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 (μgoh/mL) | 45 | 10 | 33 | | Vss(L/kg) | 2 | 5 | 0.3 | | F (%) | >90 | 80 | 18 |
Note: PO studies were performed at 10 mg/kg; MSC-4106 was formulated in 20% Kleptose in 50 mM PBS at pH 7.4.
| 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. |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | -20°C, sealed storage, away from moisture *In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture) |
| 溶解性数据 | In Vitro: DMSO : 250 mg/mL(695.80 mM;Need ultrasonic) 配制储备液 | 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 |
*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℃, 6 months; -20℃, 1 month (sealed storage, away from moisture)。-80℃ 储存时，请在 6 个月内使用，-20℃ 储存时，请在 1 个月内使用。 |
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