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KRCA-0008 exhibits drug-like characteristics without hERG liability. It is a novel, potent dual inhibitor of anaplastic lymphoma kinase (ALK) and Ack1, with IC50 values of 12 nM/4 nM for ALK and Ack1, respectively.
| Targets |
ALK (IC50 = 12 nM); Ack1 (IC50 = 4 nM)
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|---|---|
| ln Vitro |
With IC50 values of 12, 75, 4, 17, 17, and 17, respectively, KRCA-0008 (0-1000 μM) demonstrated effectiveness against ALK (wt), ALK L1196 M, ALK C1156Y, ALK F1174L, ALK R1275Q, and insulin receptor. More efficiently than crizotinib, KRCA-0008 (0-1000 nM; 4 hours) suppresses ALK-dependent signaling regulation [2]. At 210 nM, KRCA-0008 (0-1000 nM; 72 h) stimulates cells [1]. KRCA-0008 has a 48-hour half-life (0–100 nM) [2].
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| ln Vivo |
The ALK-positive Karpas-299 xenograft model is inhibited in its development by KRCA-0008 (25 and 50 mg/kg; lateral, twice daily, intermittent) [2].
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| Cell Assay |
Cell proliferation analysis [1]
Cell Types: H3122 and H1993 cell lines Tested Concentrations: 200 nM Incubation Duration: 6 hrs (hours) Experimental Results: Inhibited cell proliferation of H3122 and H1993 cells with IC50 of 0.08 and 3.6 nM respectively. Cell proliferation assay[2] Cell Types: NPM-ALK positive ALCL cell line (Karpas-299 and SU-DHL-1) and U937 NPM ALK negative lymphoma cell line Tested Concentrations: 200 nM Incubation Duration: 72 hrs (hours) Experimental Results: Proliferation was inhibited The GI50 of Karpas-299, SU-DHL-1 and U937 cells are 12 nM, 3 nM and 3.5 μM respectively. Western Blot Analysis[2] Cell Types: Karpas-299 and SU-DHL-1 Cell Lines Tested Concentrations: 0, 10, 100 and 1000 nM Incubation Duration: 4 hrs (hours) Experimental Results: Complete inhibition of phosphorylation of ALK and its effectors at dose 100 nM in NPM-ALK-positive ALCL cells. Apoptosis analysis[2] Cell Types: SU-DHL-1 Cell line Tested Concentrations: 0-1 μM Incubation Duration: 72 hrs (hours) Experimental Results: cspase-3/7 activity increased in a dose-dependent manner and induced apoptosis. Cell cycle ana |
| Animal Protocol |
Animal/Disease Models: NOD/SCID (severe combined immunodeficient) mouse with Karpas-299 xenografts [2]
Doses: 25 and 50 mg/kg Route of Administration: po (oral gavage); 25 and 50 mg/kg twice (two times) daily; two-week Experimental Results: Dramatically inhibited tumor growth by inhibiting NPM-ALK phosphorylation without exhibiting overt signs of toxicity or significant compound-related weight loss. |
| References |
|
| Molecular Formula |
C30H37CLN8O4
|
|---|---|
| Molecular Weight |
609.12
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| Exact Mass |
608.262
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| Elemental Analysis |
C, 59.16; H, 6.12; Cl, 5.82; N, 18.40; O, 10.51
|
| CAS # |
1472795-20-2
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| Related CAS # |
1472795-20-2
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| PubChem CID |
72547474
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| Appearance |
White to gray solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
870.2±75.0 °C at 760 mmHg
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| Flash Point |
480.1±37.1 °C
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| Vapour Pressure |
0.0±0.3 mmHg at 25°C
|
| Index of Refraction |
1.643
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| LogP |
0.75
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
8
|
| Heavy Atom Count |
43
|
| Complexity |
919
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C([H])N=C(N=C1N([H])C1C([H])=C([H])C(=C([H])C=1OC([H])([H])[H])N1C([H])([H])C([H])([H])N(C(C([H])([H])[H])=O)C([H])([H])C1([H])[H])N([H])C1C([H])=C([H])C(=C([H])C=1OC([H])([H])[H])N1C([H])([H])C([H])([H])N(C(C([H])([H])[H])=O)C([H])([H])C1([H])[H]
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| InChi Key |
TXDIRJCYNAWBOS-UHFFFAOYSA-N
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| InChi Code |
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)
|
| Chemical Name |
1-[4-[4-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-chloropyrimidin-4-yl]amino]-3-methoxyphenyl]piperazin-1-yl]ethanone
|
| Synonyms |
KRCA-0008; KRCA0008; KRCA 0008
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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: ~230 mg/mL (~377.6 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.75 mg/mL (9.44 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 57.5 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. Solubility in Formulation 2: ≥ 5.75 mg/mL (9.44 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 57.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 1.25 mg/mL (2.05 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.6417 mL | 8.2086 mL | 16.4171 mL | |
| 5 mM | 0.3283 mL | 1.6417 mL | 3.2834 mL | |
| 10 mM | 0.1642 mL | 0.8209 mL | 1.6417 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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