CEP-37440FAK/ALK inhibitor,potent and selective CAS# 1391712-60-9 |
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Quality Control & MSDS
3D structure
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| Cas No. | 1391712-60-9 | SDF | Download SDF |
| PubChem ID | 71721648 | Appearance | Powder |
| Formula | C30H38ClN7O3 | M.Wt | 580.12 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | DMSO : ≥ 41 mg/mL (70.68 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 2-[[5-chloro-2-[[(6S)-6-[4-(2-hydroxyethyl)piperazin-1-yl]-1-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl]amino]pyrimidin-4-yl]amino]-N-methylbenzamide | ||
| SMILES | CNC(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3=C(C4=C(CC(CCC4)N5CCN(CC5)CCO)C=C3)OC | ||
| Standard InChIKey | BCSHRERPHLTPEE-NRFANRHFSA-N | ||
| Standard InChI | InChI=1S/C30H38ClN7O3/c1-32-29(40)23-7-3-4-9-25(23)34-28-24(31)19-33-30(36-28)35-26-11-10-20-18-21(6-5-8-22(20)27(26)41-2)38-14-12-37(13-15-38)16-17-39/h3-4,7,9-11,19,21,39H,5-6,8,12-18H2,1-2H3,(H,32,40)(H2,33,34,35,36)/t21-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | CEP-37440 is a novel potent and selective Dual FAK/ALK inhibitor with IC50 s of 2.3 nM (FAK) and 120 nM(ALK cellular IC50 in 75% human plasma).
IC50 value: 2.3 nM (FAK); 120 nM (ALK cellular IC50 in 75% human plasma)
Target: Dual FAK/ALK
Preparation of fused bicyclic 2,4-diaminopyrimidine derivatives as a dual ALK and FAK inhibitor
By Jacobs, Martin J.; Ott, Gregory R.
From PCT Int. Appl. (2013), WO 2013134353 A1 20130912. References: | |||||
CEP-37440 Dilution Calculator
CEP-37440 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.7238 mL | 8.6189 mL | 17.2378 mL | 34.4756 mL | 43.0945 mL |
| 5 mM | 0.3448 mL | 1.7238 mL | 3.4476 mL | 6.8951 mL | 8.6189 mL |
| 10 mM | 0.1724 mL | 0.8619 mL | 1.7238 mL | 3.4476 mL | 4.3095 mL |
| 50 mM | 0.0345 mL | 0.1724 mL | 0.3448 mL | 0.6895 mL | 0.8619 mL |
| 100 mM | 0.0172 mL | 0.0862 mL | 0.1724 mL | 0.3448 mL | 0.4309 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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IC50: 1000 nM for the proliferation in SUM190 cell lines
The focal adhesion kinase FAK1 is a cytoplasmic tyrosine kinase that localizes to focal adhesions, and controls a number of cell pathways including proliferation, viability and survival. Anaplastic lymphoma kinase 1 (ALK-1) is a member of the insulin receptor tyrosine kinase family. ALK mutations have also been implicated in the pathogenesis of non-small cell lung cancer (NSCLC) and other solid tumors. CEP-37440 is a highly selective and potent dual inhibitor of ALK and FAK1.
In vitro: 300 nM CEP-37440 was able to decrease the proliferation of the triple negative FC-IBC02 cell line and, 1000 nM CEP-37440 was able to complete inhibit the proliferation of these cells. Genes involved in functions such as cellular growth and proliferation, cell cycle, cell death and survival and cellular movement and cell-to cell signaling and interaction were differentially regulated by CEP-37440 in sensitive IBC cell lines. Among them, TGFβ1 and MMP3 were down-regulated and DKK3, CAV1 and TFPI2 were up-regulated by CEP-37440, which might be probalby caused by its dual inhibition of ALK and FAK1 [1].
In vivo: In FC-IBC02 orthotopic breast cancer xenograft models, CEP-37440 was able to reduce the growth of the primary tumor and inhibit the development of spontaneous metastases in brain [1].
Clinical trials: CEP-37440 is a dual ALK/FAK inhibitor currently under investigation in a phase I trial to determine its MTD in patients with advanced or metastatic solid tumors (NCT01922752).
Reference:
[1] Abstract 3232: CEP-37440, a highly selective and potent dual inhibitor of ALK and FAK1 inhibits the proliferation of inflammatory breast cancer cells. Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA
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Discovery of Clinical Candidate CEP-37440, a Selective Inhibitor of Focal Adhesion Kinase (FAK) and Anaplastic Lymphoma Kinase (ALK).[Pubmed:27527804]
J Med Chem. 2016 Aug 25;59(16):7478-96.
Analogues structurally related to anaplastic lymphoma kinase (ALK) inhibitor 1 were optimized for metabolic stability. The results from this endeavor not only led to improved metabolic stability, pharmacokinetic parameters, and in vitro activity against clinically derived resistance mutations but also led to the incorporation of activity for focal adhesion kinase (FAK). FAK activation, via amplification and/or overexpression, is characteristic of multiple invasive solid tumors and metastasis. The discovery of the clinical stage, dual FAK/ALK inhibitor 27b, including details surrounding SAR, in vitro/in vivo pharmacology, and pharmacokinetics, is reported herein.
The effects of CEP-37440, an inhibitor of focal adhesion kinase, in vitro and in vivo on inflammatory breast cancer cells.[Pubmed:27009091]
Breast Cancer Res. 2016 Mar 24;18(1):37.
BACKGROUND: Inflammatory breast cancer (IBC) is an aggressive type of advanced breast cancer with a poor prognosis. We recently found that focal adhesion kinase 1 (FAK1) is upregulated and phosphorylated (active) in IBC. In this study, we investigated the effect of CEP-37440, a dual inhibitor of FAK1 and anaplastic lymphoma kinase (ALK), using human IBC cell lines and preclinical models of IBC. METHODS: Cell proliferation assays were performed in the presence of several concentrations of CEP-37440 using IBC and triple-negative breast cancer non-IBC cell lines. In vitro, we studied the expression of total FAK1, phospho-FAK1 (Tyr 397), total ALK and phospho-ALK (Tyr 1604). In vivo, we tested CEP-37440 using FC-IBC02, SUM149, and SUM190 IBC xenograft mouse models. RESULTS: CEP-37440 at low concentration decreased the proliferation of the IBC cell lines FC-IBC02, SUM190, and KPL4, while not affecting the proliferation of normal breast epithelial cells. At higher concentration, CEP-37440 was also able to inhibit the proliferation of the IBC cell line MDA-IBC03 and the triple-negative non-IBC cell lines MDA-MB-231 and MDA-MB-468; the IBC cell line SUM149 showed a slight response to the drug. CEP-37440 decreased the cell proliferation of FC-IBC02, SUM190, and KPL4 by blocking the autophosphorylation kinase activity of FAK1 (Tyr 397). None of the cells evaluated expressed ALK. In vivo, after 7 weeks of CEP-37440 treatment, the SUM190, FC-IBC02, and SUM149 breast tumor xenografts were smaller in mice treated with 55 mg/kg bid CEP-37440 compared to the controls; the tumor growth inhibition (TGI) was 79.7 %, 33 %, and 23 %, respectively. None of the FC-IBC02 breast xenografts mice treated with CEP-37440 developed brain metastasis while 20 % of the mice in the control group developed brain metastasis. Expression array analyses in FC-IBC02 cells showed that CEP-37440 affects the expression of genes related to apoptosis, interferon signaling, and cytokines. CONCLUSIONS: CEP-37440 is effective against some IBC cells that express phospho-FAK1 (Tyr 397), and its antiproliferative activity is related to its ability to decrease phospho-FAK1. Our results suggest that combinational therapies could be more effective than using CEP-37440 as a single agent.
