KRCA 0008Potent Ack1 and ALK dual inhibitor; orally bioavailable CAS# 1472795-20-2 |
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| Cas No. | 1472795-20-2 | SDF | Download SDF |
| PubChem ID | 72547474 | Appearance | Powder |
| Formula | C30H37ClN8O4 | M.Wt | 609.12 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Solubility | H2O : < 0.1 mg/mL (insoluble) | ||
| Chemical Name | 1-[4-[4-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-chloropyrimidin-4-yl]amino]-3-methoxyphenyl]piperazin-1-yl]ethanone | ||
| SMILES | CC(=O)N1CCN(CC1)C2=CC(=C(C=C2)NC3=NC(=NC=C3Cl)NC4=C(C=C(C=C4)N5CCN(CC5)C(=O)C)OC)OC | ||
| Standard InChIKey | TXDIRJCYNAWBOS-UHFFFAOYSA-N | ||
| Standard InChI | InChI=1S/C30H37ClN8O4/c1-20(40)36-9-13-38(14-10-36)22-5-7-25(27(17-22)42-3)33-29-24(31)19-32-30(35-29)34-26-8-6-23(18-28(26)43-4)39-15-11-37(12-16-39)21(2)41/h5-8,17-19H,9-16H2,1-4H3,(H2,32,33,34,35) | ||
| 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 | Potent Ack1 and anaplastic lymphoma kinase (ALK) dual inhibitor (IC50 values are 4 and 12 nM respectively). Inhibits lung cancer H3122 cell proliferation (IC50 = 80 nM). Attenuates H3122 cell xenograft tumor growth in mice. Orally bioavailable. |
KRCA 0008 Dilution Calculator
KRCA 0008 Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 1.6417 mL | 8.2086 mL | 16.4171 mL | 32.8343 mL | 41.0428 mL |
| 5 mM | 0.3283 mL | 1.6417 mL | 3.2834 mL | 6.5669 mL | 8.2086 mL |
| 10 mM | 0.1642 mL | 0.8209 mL | 1.6417 mL | 3.2834 mL | 4.1043 mL |
| 50 mM | 0.0328 mL | 0.1642 mL | 0.3283 mL | 0.6567 mL | 0.8209 mL |
| 100 mM | 0.0164 mL | 0.0821 mL | 0.1642 mL | 0.3283 mL | 0.4104 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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KRCA-0008 is a potent and selective ALK/Ack1 inhibitor with IC50 of 12 nM/4 nM for ALK and Ack1 respectively; displays drug-like properties without hERG liability. IC50 value: 12 nM/4 nM(ALK/Ack1) [1] Target: ALK/Ack1 inhibitor KRCA-0008 retains good drug-like properties: good water-solubility (54 μM in 5% DMSO–water, 150 μM in 5% DMSO–PBS buffer) with moderate plasma protein binding (93% in rat) and low brain exposure (Cbrain/Cplasma = ～0.02). It has good liver microsomal stability (% remaining after 30 min: 52% in mouse, 89% in rat, 72% in human) and little to no CYP inhibition (1A2, 2C9, 2D6, 3A4 @ 10 μM). It does not appear to cause hERG blockade (patch clamp IC50 = 30 μM) and is negative on Ames test (1000 μg/plate), chromosomal aberration assay and micronucleus assay. KRCA-0008 also shows promising pharmacokinetic parameters in both mice and rat (oral bioavailability = 66–94.5%). KRCA-0008 shows a modest tumor growth inhibition in vivo activity in H3122 human lung cancer bearing mice model comparable to Crizotinib without significant body weight change. It is important to mention the KRCA-0008 25 mpk and 50 mpk groups did not show dose-dependent tumor growth inhibition.
References:
[1]. Park CH, et al. Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment. Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6.
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Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment.[Pubmed:24095090]
Bioorg Med Chem Lett. 2013 Nov 15;23(22):6192-6.
The synthesis of bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines is described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is presented. KRCA-0008 is selective and potent to ALK and Ack1, and displays drug-like properties without hERG liability. KRCA-0008 demonstrates in vivo efficacy comparable to Crizotinib in xenograft mice model.
ALK inhibitors of bis-ortho-alkoxy-para-piperazinesubstituted-pyrimidines and -triazines for cancer treatment.[Pubmed:24446111]
Arch Pharm Res. 2014;37(9):1130-8.
Syntheses of various bis-ortho-alkoxy-para-piperazineanilino-pyrimidines and -triazines of KRCA-0008 analogs are described and their structure-activity-relationship to anaplastic lymphoma kinase (ALK) is discussed. 5-trifluoromethyl-2,4-pyrimidine analog (2) seems to be most potent in both biochemical and cellular assay in this study, however it shows inferior mice xenograft activity to Crizotinib presumably due to its sub-optimal PK parameters. 4,6-disubstituted pyrimidine and 2,4-disubstituted triazine derivatives of KRCA-0008 are less potent or inactive to ALK wt., and this observation is explained with their molecular modeling compared to KRCA-0008.
