| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| 25mg |
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| 50mg |
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| 100mg |
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| 200mg |
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| Targets |
FAK/focal adhesion kinase (pDC50 = 8.4; DC50 = 1.3 nM)
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| ln Vitro |
GSK215 has an established DC50 of 1.3 nM in A549 cells and effectively increases FAK degradation by >90% at concentrations of 0.1-1000 nM over a 2-hour period [1]. Degradation of GSK215 is mediated by ubiquitin and the proteasome [1]. The main kinases that are reduced by GSK215 (above 100 nM, 6 hours) are CDK7, RPS6KA3, MET, and GAK[1]. In A549 cells, GSK215 (100 nM, 48 hours) inhibits collagen deposition, invasion, and migration [1].
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| ln Vivo |
GSK215 (8 mg/kg; ih; once) exhibits a Cmax of 526 ng/mL and a tmax of 0.33 h in its degradation of FAK [1].
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| Enzyme Assay |
A PROTAC with an unusually short linker potently degrades focal adhesion kinase (FAK). SPR and X-ray crystallography revealed a highly cooperative FAK-PROTAC-VCB ternary complex, and FAK degradation showed enhanced effects on 3D cell growth compared to FAK inhibitors.
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[1].
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| Cell Assay |
Western Blot Analysis[1]
Cell Types: A549 cells Tested Concentrations: 0.1-1000 nM Incubation Duration: 2 h Experimental Results: Increased the FAK degradation. Cell Migration Assay [1] Cell Types: A549 cells Tested Concentrations: 100 nM Incubation Duration: 48 h Experimental Results: Inhibited cell migration. Cell Invasion Assay[1] Cell Types: A549 cells Tested Concentrations: 100 nM Incubation Duration: 48 h Experimental Results: Inhibited cell invasion. |
| Animal Protocol |
Animal/Disease Models: Male CD1 mice (P878/881A), 7-9 weeks[1]
Doses: 8 mg/kg Route of Administration: Single subcutaneous (sc) injection Experimental Results: Caused a rapid and profound degradation of FAK in liver over time, with a maximal degradation of ~85% being achieved within 18 h. Endogenous FAK was found to still be decreased by ~60% at 96 h post-dose. The Cmax and tmax were 526 ng/mL and 0.33 hrs (hours), respectively. |
| References | |
| Additional Infomation |
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.[1]
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| Molecular Formula |
C50H59F3N10O6S
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|---|---|
| Molecular Weight |
985.13
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| Exact Mass |
984.43
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| Elemental Analysis |
C, 60.96; H, 6.04; F, 5.79; N, 14.22; O, 9.74; S, 3.25
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| CAS # |
2743427-26-9
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| PubChem CID |
156600270
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
7.4
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| Hydrogen Bond Donor Count |
6
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| Hydrogen Bond Acceptor Count |
16
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| Rotatable Bond Count |
16
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| Heavy Atom Count |
70
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| Complexity |
1750
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| Defined Atom Stereocenter Count |
4
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| SMILES |
N(C1C=CC=CC=1C(=O)NC)C1=CC(NC2C=CC(N3CCN(CC(=O)N[C@@H](C(C)(C)C)C(N4C[C@H](O)C[C@H]4C(=O)N[C@H](C4C=CC(C5SC=NC=5C)=CC=4)C)=O)CC3)=CC=2OC)=NC=C1C(F)(F)F
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| InChi Key |
ZGSWGXNEXAXEGV-XFCHVEHOSA-N
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| InChi Code |
InChI=1S/C50H59F3N10O6S/c1-29(31-12-14-32(15-13-31)44-30(2)56-28-70-44)57-47(67)40-23-34(64)26-63(40)48(68)45(49(3,4)5)60-43(65)27-61-18-20-62(21-19-61)33-16-17-38(41(22-33)69-7)59-42-24-39(36(25-55-42)50(51,52)53)58-37-11-9-8-10-35(37)46(66)54-6/h8-17,22,24-25,28-29,34,40,45,64H,18-21,23,26-27H2,1-7H3,(H,54,66)(H,57,67)(H,60,65)(H2,55,58,59)/t29-,34+,40-,45+/m0/s1
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| Chemical Name |
(2S,4R)-4-hydroxy-1-[(2S)-2-[[2-[4-[3-methoxy-4-[[4-[2-(methylcarbamoyl)anilino]-5-(trifluoromethyl)pyridin-2-yl]amino]phenyl]piperazin-1-yl]acetyl]amino]-3,3-dimethylbutanoyl]-N-[(1S)-1-[4-(4-methyl-1,3-thiazol-5-yl)phenyl]ethyl]pyrrolidine-2-carboxamide
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| Synonyms |
GSK215; GSK-215; GSK215; 2743427-26-9; (2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(3-methoxy-4-((4-((2-(methylcarbamoyl)phenyl)amino)-5-(trifluoromethyl)pyridin-2-yl)amino)phenyl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-((S)-1-(4-(4-methylthiazol-5-yl)phenyl)ethyl)pyrrolidine-2-carboxamide; CHEMBL5285810; GSK215?; GSK 215;
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| 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 : ~250 mg/mL (~253.77 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (2.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (2.11 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 20.8 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 | 1.0151 mL | 5.0755 mL | 10.1509 mL | |
| 5 mM | 0.2030 mL | 1.0151 mL | 2.0302 mL | |
| 10 mM | 0.1015 mL | 0.5075 mL | 1.0151 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.
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