| Size | Price | Stock | Qty |
|---|---|---|---|
| 1mg |
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| Other Sizes |
Purity: ≥98%
| Targets |
PTK2/FAK (DC50 = 30 nM)
BI-3663 targets focal adhesion kinase (FAK), also known as PTK2. It is a PROTAC that utilizes a BI-4464-derived ligand to bind the ATP pocket of the FAK kinase domain and a cereblon ligand to recruit E3 ligases. It has an IC₅₀ of 18 nM for PTK2 inhibition and a median DC₅₀ of 30 nM for degradation. |
|---|---|
| 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].
In vitro, BI-3663 potently inhibits PTK2 with an IC₅₀ of 18 nM. It induces PTK2 degradation with a median DC₅₀ of 30 nM across a panel of eleven hepatocellular carcinoma (HCC) cell lines. It is a highly selective PTK2/FAK degrader. |
| ln Vivo |
In vivo, BI-3663 has demonstrated anticancer activity in preclinical models. By degrading PTK2/FAK, it disrupts focal adhesion signaling and inhibits tumor cell growth and metastasis. It has been studied for the treatment of hepatocellular carcinoma and other cancers.
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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]
The in vitro kinase assay for BI-3663 measures the inhibition of PTK2/FAK kinase activity. Recombinant PTK2 is incubated with the compound and a peptide substrate in the presence of ATP. The phosphorylation of the substrate is quantified. IC₅₀ values are calculated. |
| 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] In vitro cell-based assays for BI-3663 are performed using cancer cell lines, particularly HCC cell lines. Cells are treated with BI-3663, and PTK2 levels are measured by Western blotting to assess degradation. Cell proliferation, migration, and invasion are assessed. DC₅₀ values are determined. |
| Animal Protocol |
In vivo animal experiments for BI-3663 have been conducted in xenograft models of hepatocellular carcinoma. Animals are administered the compound via appropriate routes, and tumor growth inhibition is measured. PTK2 degradation in tumor tissues is confirmed by Western blotting.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of BI-3663 have been characterized in preclinical species. It achieves sufficient plasma concentrations to exert its pharmacological effects. Detailed PK parameters such as half-life, clearance, and bioavailability are determined from plasma concentration-time profiles.
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| Toxicity/Toxicokinetics |
Toxicological data for BI-3663 are limited. In standard preclinical safety assessments, it would be evaluated for potential off-target effects and general toxicity. The compound is intended for research use only and not for therapeutic use in humans.
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| References | |
| Additional Infomation |
Adhesion tyrosine kinase 2 (PTK2) is often overexpressed in human hepatocellular carcinoma (HCC), and multiple studies have shown that the loss and/or pharmacological inhibition of PTK2 can reduce tumor incidence. However, the clinical significance of targeting PTK2 remains to be confirmed. This article reports two highly selective and functional PTK2 proteolytic targeting chimeras that utilize von Hippel-Lindau and cereblon ligands to hijack E3 ligases to degrade PTK2. BI-3663 (cereblon-based) showed a median PTK2 degradation rate (DC50) of 30 nM in 11 HCC cell lines, with a degradation rate exceeding 80%. Despite the effective degradation of PTK2, these compounds did not show antiproliferative effects associated with PTK2 loss in any of the cell lines tested. By publishing these compounds, we hope to provide valuable tools for studying PTK2 degradation in different biological systems. [1]
BI-3663 is a first-in-class PROTAC degrader of PTK2/FAK that has shown promise for the treatment of hepatocellular carcinoma. It represents a novel therapeutic strategy for targeting FAK in cancer. It has not been approved for clinical use. |
| Molecular Formula |
C44H42F3N7O12
|
|---|---|
| Molecular Weight |
917.839201450348
|
| Exact Mass |
917.284
|
| 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
|
| Density |
1.5±0.1 g/cm3
|
| Index of Refraction |
1.627
|
| LogP |
2.31
|
| Hydrogen Bond Donor Count |
4
|
| Hydrogen Bond Acceptor Count |
18
|
| Rotatable Bond Count |
20
|
| Heavy Atom Count |
66
|
| Complexity |
1760
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
COC1=C(C=CC(=C1)C(=O)NCCOCCOCCOCCC(=O)NC2=CC=CC3=C2C(=O)N(C3=O)C4CCC(=O)NC4=O)NC5=NC=C(C(=N5)OC6=CC=CC7=C6C(=O)CC7)C(F)(F)F
|
| InChi Key |
ADTXLFJKQHYGPM-UHFFFAOYSA-N
|
| 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)
|
| 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
|
| 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;
|
| 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)
|
| 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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