| Size | Price | Stock | Qty |
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| 1mg |
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Purity: ≥98%
BI-3663 is a novel, potent, functional and highly selective PTK2/FAK degrader based on PROTAC (proteolysis-targeting chimeras) technology, utilizing VHL (von Hippel-Lindau) and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 inhibits PTK2 with an IC50 of 18 nM. Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested.
| Targets |
PTK2/FAK (DC50 = 30 nM)
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|---|---|
| ln Vitro |
In Hep3B2.1-7 cells and A549 cells, BI-3663 can efficiently degrade PTK2, with pDC50s of 7.6 and 7.9, respectively [1].
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| Enzyme Assay |
Researchers employed multiplexed isobaric tagging mass spectrometry to assess the cellular selectivity of BI-3663 (6) and BI-0319 (8) for PTK2 degradation and identify potential degradation off-targets in a quantitative and unbiased manner. Among the 6008 proteins quantified in this analysis in A549 cells, PTK2 showed a distinct and significant change in abundance upon treatment with either PROTAC (Figure 4 and Table S3). Neither BI-3663 (6) nor BI-0319 (8) induced any significant changes in abundance of other detectable kinases, thus confirming the high selectivity of both degraders within the kinase family. Of note, the two most prominent kinase off-targets of the inhibitor were not detected in this dataset. Interestingly, BI-0319 (8)—but not BI-3663 (6)—also induced a significant change of PDE6D levels (Figure 4A), a finding corroborated by an immunoblot in the A549 cells (Figure S1).[1]
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| Cell Assay |
A549 cells were treated with increasing concentrations (100 nM to 10 µM) of BI-4206 (the cis-VHL control for BI-0319), BI-0319 and BI-3663 for 18 h. PTK2 and PDE6D levels were determined by protein capillary electrophoresis.[1]
The indicated HCC cell lines were treated with increasing concentrations (10 nM to 25 µM) of BI-0319 for 18 h. PTK2 levels were determined by protein capillary electrophoresis and normalized to GAPDH. Values are stated as percent of DMSO controls (POC). Dose response curves were determined using a four parameter (variable slope) inhibition model using GraphPad Prism. Increasing PTK2 levels occurring beyond the hook point caused by preferential formation of binary complexes at high PROTAC concentrations were excluded from the analysis.[1] The indicated HCC cell lines were treated with increasing concentrations (10 nM to 25 µM) of BI-3663 for 18 h. PTK2 levels were determined by protein capillary electrophoresis and normalized to GAPDH. Values are stated as percent of DMSO controls (POC). Dose response curves were determined using a four parameter (variable slope) inhibition model using GraphPad Prism. Increasing PTK2 levels occurring beyond the hook point caused by preferential formation of binary complexes at high PROTAC concentrations were excluded from the analysis. [1] The indicated HCC cell lines were treated with increasing concentrations (10 nM to 25 µM) of BI-3663, BI-0319, the PTK2 kinase inhibitor BI-4464 or doxorubicine as a positive control for 6 days. At the end of the incubation cell viability was measured by luminescence-based viability assay. DMSO indicates the signal obtained with DMSO controls, T0 indicates the signal obtained prior to addition of the compounds.[1] |
| References | |
| Additional Infomation |
Focal adhesion tyrosine kinase (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and several reports have linked PTK2 depletion and/or pharmacological inhibition to reduced tumorigenicity. However, the clinical relevance of targeting PTK2 still remains to be proven. Here, we present two highly selective and functional PTK2 proteolysis-targeting chimeras utilizing von Hippel-Lindau and cereblon ligands to hijack E3 ligases for PTK2 degradation. BI-3663 (cereblon-based) degrades PTK2 with a median DC50 of 30 nM to >80% across a panel of 11 HCC cell lines. Despite effective PTK2 degradation, these compounds did not phenocopy the reported antiproliferative effects of PTK2 depletion in any of the cell lines tested. By disclosing these compounds, we hope to provide valuable tools for the study of PTK2 degradation across different biological systems.[1]
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| Molecular Formula |
C44H42F3N7O12
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|---|---|
| Molecular Weight |
917.839201450348
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| Exact Mass |
917.284
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| Elemental Analysis |
C, 57.58; H, 4.61; F, 6.21; N, 10.68; O, 20.92
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| CAS # |
2341740-84-7
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| PubChem CID |
137628657
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Index of Refraction |
1.627
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| LogP |
2.31
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
18
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| Rotatable Bond Count |
20
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| Heavy Atom Count |
66
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| Complexity |
1760
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ADTXLFJKQHYGPM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C44H42F3N7O12/c1-62-33-22-25(8-10-28(33)51-43-49-23-27(44(45,46)47)40(53-43)66-32-7-2-4-24-9-12-31(55)36(24)32)38(58)48-15-17-64-19-21-65-20-18-63-16-14-35(57)50-29-6-3-5-26-37(29)42(61)54(41(26)60)30-11-13-34(56)52-39(30)59/h2-8,10,22-23,30H,9,11-21H2,1H3,(H,48,58)(H,50,57)(H,49,51,53)(H,52,56,59)
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| Chemical Name |
-[2-[2-[2-[3-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethyl]-3-methoxy-4-[[4-[(3-oxo-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide
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| Synonyms |
BI-3663; BI3663; 2341740-84-7; CHEMBL4781145; N-[2-[2-[2-[3-[[2-(2,6-Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]-3-oxopropoxy]ethoxy]ethoxy]ethyl]-3-methoxy-4-[[4-[(3-oxo-1,2-dihydroinden-4-yl)oxy]-5-(trifluoromethyl)pyrimidin-2-yl]amino]benzamide;
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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 : ~300 mg/mL (~326.85 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 7.5 mg/mL (8.17 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 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 75.0 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.0895 mL | 5.4476 mL | 10.8951 mL | |
| 5 mM | 0.2179 mL | 1.0895 mL | 2.1790 mL | |
| 10 mM | 0.1090 mL | 0.5448 mL | 1.0895 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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