ALK inhibitor 2

ALK inhibitor, novel and selective CAS# 761438-38-4

ALK inhibitor 2

Catalog No. BCC1340----Order now to get a substantial discount!

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Chemical structure

ALK inhibitor 2

3D structure

Chemical Properties of ALK inhibitor 2

Cas No. 761438-38-4 SDF Download SDF
PubChem ID 66577032 Appearance Powder
Formula C23H28ClN7O3S M.Wt 518.03
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (96.52 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino]pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide
SMILES CNS(=O)(=O)C1=CC=CC=C1NC2=NC(=NC=C2Cl)NC3=C(C=C(C=C3)N4CCN(CC4)C)OC
Standard InChIKey NURCYJBMLKNYHB-UHFFFAOYSA-N
Standard InChI InChI=1S/C23H28ClN7O3S/c1-25-35(32,33)21-7-5-4-6-19(21)27-22-17(24)15-26-23(29-22)28-18-9-8-16(14-20(18)34-3)31-12-10-30(2)11-13-31/h4-9,14-15,25H,10-13H2,1-3H3,(H2,26,27,28,29)
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.
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.
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.

Biological Activity of ALK inhibitor 2

DescriptionALK inhibitor 2 is a novel and selective inhibitor for the ALK kinase.

References:
[1]. A Dose Finding Study With Oral LDK378 in Patients With Tumors Characterized by Genetic Abnormalities in Anaplastic Lymphoma Kinase (ALK).

ALK inhibitor 2 Dilution Calculator

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ALK inhibitor 2 Molarity Calculator

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Preparing Stock Solutions of ALK inhibitor 2

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9304 mL 9.652 mL 19.3039 mL 38.6078 mL 48.2598 mL
5 mM 0.3861 mL 1.9304 mL 3.8608 mL 7.7216 mL 9.652 mL
10 mM 0.193 mL 0.9652 mL 1.9304 mL 3.8608 mL 4.826 mL
50 mM 0.0386 mL 0.193 mL 0.3861 mL 0.7722 mL 0.9652 mL
100 mM 0.0193 mL 0.0965 mL 0.193 mL 0.3861 mL 0.4826 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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Background on ALK inhibitor 2

ALK inhibitors are potential anti-cancer drugs that act on tumours with variations of anaplastic lymphoma kinase (ALK) such as an EML4-ALK [1]. As the same as ALK inhibitor 1, ALK inhibitor 2 is a novel and selective inhibitor for the ALK kinase as well.
In vitro: ALK inhibitor 2 (2-[[5-chloro-2-[2-methoxy-4-(4-methylpiperazin-1-yl)anilino] pyrimidin-4-yl]amino]-N-methylbenzenesulfonamide) is a chemical analogue of LDK378 that is a potent ALK inhibitor [2].
In vivo: No animal in-vivo data available currently.
Clinical trial: Currently ALK inhibitor 2 is only in the preclinical developlent stage and no clinical data are available.
Reference:
[1] Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420(3):345-61.
[2] Marsilje TH, Pei W, Chen B, Lu W, et al. Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulfonyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials. J Med Chem. 2013;56(14):5675-90.

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References on ALK inhibitor 2

Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing bicyclic aminobenzazepines for anaplastic lymphoma kinase (ALK) inhibitor.[Pubmed:26235945]

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3992-8.

A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.

Discovery of (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4-(m etheno)pyrazolo[4,3-h][2,5,11]-benzoxadiazacyclotetradecine-3-carbonitrile (PF-06463922), a macrocyclic inhibitor of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) with preclinical brain exposure and broad-spectrum potency against ALK-resistant mutations.[Pubmed:24819116]

J Med Chem. 2014 Jun 12;57(11):4720-44.

Although crizotinib demonstrates robust efficacy in anaplastic lymphoma kinase (ALK)-positive non-small-cell lung carcinoma patients, progression during treatment eventually develops. Resistant patient samples revealed a variety of point mutations in the kinase domain of ALK, including the L1196M gatekeeper mutation. In addition, some patients progress due to cancer metastasis in the brain. Using structure-based drug design, lipophilic efficiency, and physical-property-based optimization, highly potent macrocyclic ALK inhibitors were prepared with good absorption, distribution, metabolism, and excretion (ADME), low propensity for p-glycoprotein 1-mediated efflux, and good passive permeability. These structurally unusual macrocyclic inhibitors were potent against wild-type ALK and clinically reported ALK kinase domain mutations. Significant synthetic challenges were overcome, utilizing novel transformations to enable the use of these macrocycles in drug discovery paradigms. This work led to the discovery of 8k (PF-06463922), combining broad-spectrum potency, central nervous system ADME, and a high degree of kinase selectivity.

Synthesis, structure-activity relationships, and in vivo efficacy of the novel potent and selective anaplastic lymphoma kinase (ALK) inhibitor 5-chloro-N2-(2-isopropoxy-5-methyl-4-(piperidin-4-yl)phenyl)-N4-(2-(isopropylsulf onyl)phenyl)pyrimidine-2,4-diamine (LDK378) currently in phase 1 and phase 2 clinical trials.[Pubmed:23742252]

J Med Chem. 2013 Jul 25;56(14):5675-90.

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Importance of protein flexibility in ranking inhibitor affinities: modeling the binding mechanisms of piperidine carboxamides as Type I1/2 ALK inhibitors.[Pubmed:25644934]

Phys Chem Chem Phys. 2015 Feb 28;17(8):6098-113.

Anaplastic lymphoma kinase (ALK) has gained increased attention as an attractive therapeutic target for the treatment of various cancers, especially non-small-cell lung cancer (NSCLC). Recently, piperidine carboxamides were reported as Type I1/2 inhibitors of ALK, which occupy both the ATP binding site and the back ATP hydrophobic cavity in DFG-in conformation. Due to the dynamic behavior of ALK in the binding of Type I1/2 inhibitors, the accurate predictions of the binding structures and relative binding potencies of these inhibitors are quite challenging. In this study, different modeling techniques, including molecular docking, ensemble docking based on multiple receptor conformations, molecular dynamics simulations and free energy calculations, were utilized to explore the binding mechanisms of piperidine carboxamides. Our predictions show that the conventional docking protocols are not sufficient to predict the relative binding potencies of the studied inhibitors with high accuracy, but incorporating protein flexibility before or after docking is quite effective to improve the prediction accuracy. Notably, the binding free energies predicted by MM/GBSA or MM/PBSA based on the MD simulations for the docked poses give the highest correlation with the experimental data, highlighting the importance of the inclusion of receptor flexibility for the accurate predictions of the binding potencies for Type I1/2 inhibitors of ALK. Furthermore, the comprehensive analysis of several pairs of representative inhibitors demonstrates the importance of hydrophobic interactions in improving the binding affinities of the inhibitors with the hot-spot residues surrounding the binding pocket. This work is expected to provide valuable clues for further rational design of novel and potent Type I1/2 ALK inhibitors.

Description

ALK inhibitor 2 is a novel and selective inhibitor for the ALK kinase.

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