GSK215
目录号 : GC64888
GSK215 is a potent and selective PROTAC focal adhesion kinase (FAK) degrader, which exerts FAK degradation in A549 non-small-cell lung cancer cells with DC50 of 1.3 nM by a strong time-dependence way and maximal degradation (Dmax) near the limit of the assay quantification (Dmax 99%).
Cas No.:2743427-26-9
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
GSK215 is a potent and selective PROTAC focal adhesion kinase (FAK) degrader, which exerts FAK degradation in A549 non-small-cell lung cancer cells with DC50 of 1.3 nM by a strong time-dependence way and maximal degradation (Dmax) near the limit of the assay quantification (Dmax 99%).
[1] Law RP, et al. Angew Chem Int Ed Engl. 2021 Oct 18;60(43):23327-23334.
| Cas No. | 2743427-26-9 | SDF | Download SDF |
| 分子式 | C50H59F3N10O6S | 分子量 | 985.13 |
| 溶解度 | DMSO : 250 mg/mL (253.77 mM; Need ultrasonic) | 储存条件 | Store at -20°C |
| 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 | 1.0151 mL | 5.0755 mL | 10.1509 mL |
| 5 mM | 0.203 mL | 1.0151 mL | 2.0302 mL |
| 10 mM | 0.1015 mL | 0.5075 mL | 1.0151 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。
Discovery and Characterisation of Highly Cooperative FAK-Degrading PROTACs
Angew Chem Int Ed Engl 2021 Oct 18;60(43):23327-23334.PMID:34416073DOI:10.1002/anie.202109237.
Focal adhesion kinase (FAK) is a key mediator of tumour progression and metastasis. To date, clinical trials of FAK inhibitors have reported disappointing efficacy for oncology indications. We report the design and characterisation of GSK215, a potent, selective, FAK-degrading Proteolysis Targeting Chimera (PROTAC) based on a binder for the VHL E3 ligase and the known FAK inhibitor VS-4718. X-ray crystallography revealed the molecular basis of the highly cooperative FAK-GSK215-VHL ternary complex, and GSK215 showed differentiated in-vitro pharmacology compared to VS-4718. In mice, a single dose of GSK215 induced rapid and prolonged FAK degradation, giving a long-lasting effect on FAK levels (≈96 h) and a marked PK/PD disconnect. This tool PROTAC molecule is expected to be useful for the study of FAK-degradation biology in vivo, and our results indicate that FAK degradation may be a differentiated clinical strategy versus FAK inhibition for the treatment of cancer.
Discovery of GSK251: A Highly Potent, Highly Selective, Orally Bioavailable Inhibitor of PI3Kδ with a Novel Binding Mode
J Med Chem 2021 Sep 23;64(18):13780-13792.PMID:34510892DOI:10.1021/acs.jmedchem.1c01102.
Optimization of a previously reported lead series of PI3Kδ inhibitors with a novel binding mode led to the identification of a clinical candidate compound 31 (GSK251). Removal of an embedded Ames-positive heteroaromatic amine by reversing a sulfonamide followed by locating an interaction with Trp760 led to a highly selective compound 9. Further optimization to avoid glutathione trapping, to enhance potency and selectivity, and to optimize an oral pharmacokinetic profile led to the discovery of compound 31 (GSK215) that had a low predicted daily dose (45 mg, b.i.d) and a rat toxicity profile suitable for further development.