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| Targets |
ALK (IC50 = 12 nM); Ack1 (IC50 = 4 nM)
KRCA-0008 targets two distinct kinases: anaplastic lymphoma kinase (ALK) and activated Cdc42-associated kinase 1 (ACK1, also known as TNK2). ALK is a receptor tyrosine kinase that, when activated through mutation, amplification, or chromosomal translocation, drives oncogenesis in several cancers, notably non-small cell lung cancer and anaplastic large cell lymphoma. ACK1 is a non-receptor tyrosine kinase that plays a critical role in cell proliferation, survival, and migration, and its overexpression or mutation is implicated in various cancers. KRCA-0008 acts as a potent dual inhibitor by binding to the ATP-binding pocket of both kinases, thereby blocking their enzymatic activity and downstream signaling pathways. |
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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].
In vitro, KRCA-0008 demonstrates potent enzymatic inhibition against its targets. It inhibits ALK with an IC₅₀ of 12 nM and ACK1 with an IC₅₀ of 4 nM. This high potency translates into significant cellular activity, as the compound inhibits the proliferation of H3122 lung cancer cells, a model for ALK-driven cancers, with an IC₅₀ of 80 nM. The compound's ability to effectively inhibit these two kinases highlights its potential as a potent anticancer agent and a valuable research tool for studying the combined roles of ALK and ACK1 in cancer biology. |
| 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].
Detailed in vivo activity data for KRCA-0008 are not extensively reported in the available literature. However, as a potent and selective inhibitor of both ALK and ACK1 with favorable drug-like properties, it is expected to have in vivo efficacy in tumor models. The compound's dual targeting of these two clinically relevant kinases suggests potential for significant antitumor activity in vivo. Further in vivo studies, such as xenograft models, would be required to fully characterize its therapeutic potential. |
| Enzyme Assay |
Non-cell-based in vitro assays for KRCA-0008 typically involve kinase activity assays using purified recombinant ALK and ACK1 enzymes. The compound is incubated with the kinase, a peptide substrate, and ATP at varying concentrations. Kinase activity is measured by quantifying substrate phosphorylation using techniques such as radiometric detection (e.g., ³³P-ATP incorporation), fluorescence polarization, or ELISA-based detection. IC₅₀ values, such as the 12 nM and 4 nM for ALK and ACK1 respectively, are determined from dose-response curves. Selectivity profiling against a panel of other kinases is performed to confirm specificity.
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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 Cellular assays for KRCA-0008 are performed using various cancer cell lines, particularly those driven by ALK or ACK1, such as H3122 lung cancer cells. Cells are treated with the compound at various concentrations for specified durations. Cell proliferation is assessed using standard viability assays such as MTT or CellTiter-Glo. The compound's ability to inhibit cell growth is quantified, and an IC₅₀ value, such as the 80 nM for H3122 cells, is determined. Mechanistic studies involve Western blotting to assess the inhibition of ALK and ACK1 phosphorylation and downstream signaling pathways. |
| 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. In vivo animal models for KRCA-0008 would be required to assess its therapeutic potential. Based on its mechanism as an ALK and ACK1 dual inhibitor, relevant models could include xenograft studies in immunodeficient mice bearing ALK-driven or ACK1-driven cancer cell lines. The compound would be administered via appropriate routes (e.g., oral gavage) at various doses. Tumor growth inhibition would be monitored over time. Pharmacodynamic markers such as ALK and ACK1 phosphorylation in tumor tissues would be assessed to confirm target engagement. Detailed protocols are not extensively reported in the available literature. |
| ADME/Pharmacokinetics |
KRCA-0008 has a molecular weight of 609.12 g/mol and a molecular formula of C₃₀H₃₇ClN₈O₄. Its CAS number is 1472795-20-2. The compound is supplied as a solid with a purity of ≥96.2%. It is soluble in DMSO. Storage conditions: -20°C. The compound exhibits drug-like properties without hERG liability, suggesting a favorable pharmacokinetic profile for a kinase inhibitor, including good bioavailability and metabolic stability. Detailed pharmacokinetic parameters such as half-life, Cmax, and volume of distribution are not extensively reported.
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| Toxicity/Toxicokinetics |
Detailed toxicological data for KRCA-0008 are not extensively reported in the available literature. The compound is noted to exhibit drug-like properties without hERG liability, which suggests a reduced risk of cardiac toxicity, a common concern with kinase inhibitors. As a research compound, its full safety profile would need to be established through standard preclinical toxicity assessments. The compound is intended for research use only and is not for human consumption. Standard laboratory safety precautions should be followed when handling the compound.
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| References |
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| Additional Infomation |
KRCA-0008 is also known by its chemical name 1,1'-(4,4'-(((5-chloropyrimidine-2,4-diyl)bis(azanediyl))bis(3-methoxy-4,1-phenylene))bis(piperazine-4,1-diyl))diethanone. It is a potent, selective dual inhibitor of ALK and ACK1 with IC₅₀ values of approximately 12 nM and 4 nM, respectively. The compound inhibits the proliferation of H3122 lung cancer cells with an IC₅₀ of 80 nM. It displays drug-like properties without hERG liability. KRCA-0008 is a valuable research tool for studying the roles of ALK and ACK1 in cancer and for developing novel anticancer therapies. It is intended for laboratory research use only.
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| Molecular Formula |
C30H37CLN8O4
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|---|---|
| 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
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| 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
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| Index of Refraction |
1.643
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| LogP |
0.75
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
43
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| 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)
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| Chemical Name |
1-[4-[4-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-chloropyrimidin-4-yl]amino]-3-methoxyphenyl]piperazin-1-yl]ethanone
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| 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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