| Size | Price | Stock | Qty |
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| Targets |
FAK (focal adhesion kinase) and ALK (anaplastic lymphoma kinase). CEP-37440 inhibits FAK with an IC50 of 2.3 nM and ALK with an IC50 of 3.5 nM. It shows cellular IC50s of 120 nM for ALK in 75% human plasma and 2.3 nM for FAK. CEP-37440 exhibits a Kd value of 3.6 nM for ALK (WT). It is a potent, selective, and brain penetrant dual FAK/ALK inhibitor with IC50 of 2.0/3.1 nM, respectively. CEP-37440 binds to and inhibits ALK and FAK, resulting in decreased downstream signaling and reduced tumor growth.
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| ln Vitro |
In a dose-dependent manner, CEP-37440 (0-3000 nM; 0-192 h) inhibits the growth of IBC cells [1]. In FC-IBC02, SUM 190, and KPL4, CEP-37440 (1000 nM; 0-120 h) decreases phosphorylated FAK1 (Tyr 397) and keeps levels low over time[1]. To encourage CEP-37440 (0-3000 nM; Sup-M2 and Karpas-299 cells), dose-dependent induction was used.
CEP-37440 decreases the proliferation of inflammatory breast cancer (IBC) cells in a dose-dependent manner. It decreases phospho-FAK1 (Tyr 397) and maintains its low level. It shows cytotoxicity against human KARPAS-299 cells expressing NPM-ALK (IC50 = 131 nM) and inhibits EML4-ALK tyrosine phosphorylation in NCI-H2228 cells (IC50 = 175 nM). CEP-37440 was able to inhibit the proliferation of certain IBC cells by decreasing the levels of phospho-FAK1 (Tyr 397); none of the cells expressed ALK. In a direct head-to-head study evaluating six clinical-stage FAK inhibitors against five pancreatic tumor cell lines (MIA Paca-2, BxPC-3, Capan-1, AsPC-1, Beta-TC-3), CEP-37440 showed activity. |
| ln Vivo |
In Sup-M2 xenograft protein SCID mice, CEP-37440 (3-55 mg/kg; sidewall bid and qd for 12 days) suppresses the formation of breast tumors [2]. In Sup-M2 xenograft mouse tumors, CEP-37440 (30 mg/kg; once lateral for 24 hours) suppresses tyrosine phosphorylation [2]. CEP-37440 (1-10 mg/kg; po and i.v.; CD-1 model, Sprague-Dawley (SD) form) has acceptable pharmacokinetic properties and suppresses FAK phosphorylation in nude CWR22 xenograft mice tumors (55 mg/kg; once lateral for 24 hours) [2].
CEP-37440 is an orally bioactive dual FAK/ALK inhibitor. It is brain penetrant, suggesting it can cross the blood-brain barrier. In vivo efficacy has been demonstrated in preclinical models, although specific study details are not provided in the references. Its dual inhibition of FAK and ALK provides a unique approach to cancer treatment. CEP-37440 has advanced to Phase 1 clinical evaluation in solid tumors. |
| Enzyme Assay |
Specific protocols for in vitro enzyme assays for CEP-37440 are not detailed in the provided references. As a kinase inhibitor, its activity would typically be assessed using biochemical kinase assays that measure the inhibition of FAK and ALK enzymatic activity, often using recombinant proteins and radiolabeled or fluorescent substrates. CEP-37440 inhibits FAK with an IC50 of 2.3 nM and ALK with an IC50 of 3.5 nM.
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| Cell Assay |
cell viability assay [1]
Cell Types: FC-IBC02, KPL4, SUM190, MDA-IBC03 and SUM149 Cell Tested Concentrations: 0, 300, 1000, 2000 and 3000 nM Incubation Duration: 0. , 24, 48, 72, 96, 120, 144, 168 and 192 hrs (hours) Experimental Results: diminished proliferation of IBC cell lines by three-fifths at low concentrations. Proliferation is almost completely inhibited at a concentration of 3000 nM. Western Blot Analysis[1] Cell Types: FC-IBC02, SUM 190 and KPL4 Cell Tested Concentrations: 1000 nM Incubation Duration: 0, 48, 72, 96 and 120 hrs (hours) Experimental Results: Phospho-FAK1 in FC-IBC02, SUM190 diminished by half and KPL4 cells after 48 hrs (hours). Cellular assays for CEP-37440 involve treating cancer cell lines with the compound and measuring cell proliferation, viability, and signaling pathway inhibition. For example, its effect on cell growth inhibition is assessed in KARPAS-299, NCI-H2228, and NCI-H3122 cells. The inhibition of FAK1 autophosphorylation (Tyr 397) is also evaluated. CEP-37440 shows cytotoxicity against human KARPAS-299 cells expressing NPM-ALK (IC50 = 131 nM) and inhibits EML4-ALK tyrosine phosphorylation in NCI-H2228 cells (IC50 = 175 nM). |
| Animal Protocol |
In vivo animal model protocols for CEP-37440 typically involve oral administration to tumor-bearing mice. The compound's antitumor efficacy, pharmacokinetic properties, and brain penetration are evaluated. Specific study details are not provided in the references, but the compound is described as orally active and brain penetrant. CEP-37440 has advanced to Phase 1 clinical evaluation in solid tumors.
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| ADME/Pharmacokinetics |
CEP-37440 is an orally active compound with favorable pharmacokinetic properties for oral administration. It is also described as brain penetrant, indicating it can cross the blood-brain barrier. In addition to a favorable metabolic stability and pharmacokinetic profile preclinically, CEP-37440 is also a brain penetrant. Specific PK parameters are not detailed in the provided references.
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| Toxicity/Toxicokinetics |
Specific toxicological data for CEP-37440 is not available in the provided references. As a clinical candidate, its safety profile is being evaluated in Phase 1 clinical trials. CEP-37440 is currently under investigation in a phase I trial to determine its MTD in patients with advanced or metastatic solid tumors (NCT01922752). The trial results demonstrated that CEP-37440 was well-tolerated and showed promising anti-tumor activity.
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| References |
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| Additional Infomation |
CEP-37440 has been used in clinical trials for the treatment of solid tumors. The ALK-FAK inhibitor CEP-37440 is an orally administered dual kinase inhibitor that inhibits receptor tyrosine kinases anaplastic lymphoma kinase (ALK) and focal adhesion kinase (FAK), exhibiting potential antitumor activity. After administration, the ALK-FAK inhibitor CEP-37440 selectively binds to and inhibits both ALK and FAK kinases. This inhibition leads to the disruption of ALK and FAK-mediated signal transduction pathways, ultimately inhibiting the growth of ALK and FAK-overexpressing tumor cells. ALK belongs to the insulin receptor superfamily and plays an important role in nervous system development; its dysregulation and gene rearrangement are associated with various tumors. Cytoplasmic tyrosine kinase FAK is an integrin signaling molecule that is upregulated and persistently activated in various tumor types; it plays a crucial role in tumor cell migration, proliferation, survival, and tumor angiogenesis.
CEP-37440 is a research compound that has advanced to clinical evaluation. It is a dual FAK/ALK inhibitor not yet approved for clinical use. Its dual inhibition of FAK and ALK makes it a unique tool for studying cancers where both pathways are important, such as inflammatory breast cancer. The compound's brain penetrance suggests potential for treating brain metastases. CEP-37440 is currently under investigation in a phase I trial to determine its MTD in patients with advanced or metastatic solid tumors (NCT01922752). |
| Molecular Formula |
C30H38CLN7O3
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|---|---|
| Molecular Weight |
580.12
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| Exact Mass |
579.272
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| CAS # |
1391712-60-9
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| PubChem CID |
71721648
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.3±0.1 g/cm3
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| Index of Refraction |
1.648
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| LogP |
3.4
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
41
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| Complexity |
819
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CNC(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3=C(C4=C(C[C@H](CCC4)N5CCN(CC5)CCO)C=C3)OC
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| InChi Key |
BCSHRERPHLTPEE-NRFANRHFSA-N
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| InChi Code |
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
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| 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
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| Synonyms |
CEP-37440; CEP 37440; CEP37440
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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 : ~100 mg/mL (~172.38 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.31 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (4.31 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.31 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7238 mL | 8.6189 mL | 17.2378 mL | |
| 5 mM | 0.3448 mL | 1.7238 mL | 3.4476 mL | |
| 10 mM | 0.1724 mL | 0.8619 mL | 1.7238 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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