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.
Physicochemical Properties
| Molecular Formula | C30H37CLN8O4 |
| Molecular Weight | 609.12 |
| Exact Mass | 608.262 |
| Elemental Analysis | C, 59.16; H, 6.12; Cl, 5.82; N, 18.40; O, 10.51 |
| CAS # | 1472795-20-2 |
| Related CAS # | 1472795-20-2 |
| PubChem CID | 72547474 |
| Appearance | White to gray solid powder |
| Density | 1.3±0.1 g/cm3 |
| Boiling Point | 870.2±75.0 °C at 760 mmHg |
| Flash Point | 480.1±37.1 °C |
| Vapour Pressure | 0.0±0.3 mmHg at 25°C |
| Index of Refraction | 1.643 |
| LogP | 0.75 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 10 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 43 |
| Complexity | 919 |
| Defined Atom Stereocenter Count | 0 |
| 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] |
| InChi Key | TXDIRJCYNAWBOS-UHFFFAOYSA-N |
| 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 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | ALK (IC50 = 12 nM); Ack1 (IC50 = 4 nM) |
| 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]. |
| 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]. |
| 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 |
[1]. 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. [2]. KRCA-0008 suppresses ALK-positive anaplastic large-cell lymphoma growth. Invest New Drugs. 2020 Oct;38(5):1282-1291. |
Solubility Data
| Solubility (In Vitro) | DMSO: ~230 mg/mL (~377.6 mM) |
| 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. 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. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 12.5 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |