 Chemical Structure.png)
Lestaurtinib (CEP-701; KT-5555; SP-924) is a novel, orally bioavailable and potent multi-kinase inhibitor with anticancer and anti-inflammatory activity. It acts by inhibiting Trk family of receptor tyrosine kinases with IC50s of 0.9, 3 and less than 25 nM for JAK2, FLT3 and TrkA, respectively. Lestaurtinib inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3.
Physicochemical Properties
| Molecular Formula | C26H21N3O4 |
| Molecular Weight | 439.46 |
| Exact Mass | 439.153 |
| CAS # | 111358-88-4 |
| PubChem CID | 126565 |
| Appearance | White to off-white solid powder |
| Density | 1.7±0.1 g/cm3 |
| Boiling Point | 723.0±60.0 °C at 760 mmHg |
| Melting Point | 215-220ºC |
| Flash Point | 391.0±32.9 °C |
| Vapour Pressure | 0.0±2.5 mmHg at 25°C |
| Index of Refraction | 1.880 |
| LogP | 3.37 |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 4 |
| Rotatable Bond Count | 1 |
| Heavy Atom Count | 33 |
| Complexity | 886 |
| Defined Atom Stereocenter Count | 3 |
| SMILES | C[C@@]12[C@](C[C@@H](O1)N3C4=CC=CC=C4C5=C6C(=C7C8=CC=CC=C8N2C7=C53)CNC6=O)(CO)O |
| InChi Key | UIARLYUEJFELEN-LROUJFHJSA-N |
| InChi Code | InChI=1S/C26H21N3O4/c1-25-26(32,12-30)10-18(33-25)28-16-8-4-2-6-13(16)20-21-15(11-27-24(21)31)19-14-7-3-5-9-17(14)29(25)23(19)22(20)28/h2-9,18,30,32H,10-12H2,1H3,(H,27,31)/t18-,25+,26+/m1/s1 |
| Chemical Name | (5S,6S,8R)-6-hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one |
| Synonyms | CEP701; KT 5555; SP924; CEP-701; KT-5555; SP-924; CEP 701; KT5555; SP 924. |
| 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 Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| 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 |
|
|
| ln Vitro | The proliferation of ATC cells is inhibited by lestaurtinib (0.01-10 µM; 72 h), with IC50 values of 0.21, 0.41, and 2.35 µM for KMH2, CAL62, and THJ-21T cells, respectively [1]. Lestaurtinib (0.125-4 µM; 24 h) totally inhibits pSTAT5 expression at 4 µM and decreases STAT5 phosphorylation in a concentration-dependent manner [1]. On WI-38, CAL62, and KMH2 cells, lestaurtinib (0.5 µM; 24 hours) exhibits anti-proliferative effects [1]. In CAL62 and KMH2 cells, lestaturtinib (4 μM; 24 hours) causes cell cycle arrest in the G2/M phase [1]. Lestaurtinib (30-300 nM; 48 hours) causes apoptosis in HL (Hodgkin lymphoma) cell lines in a dose-dependent manner [2]. At 300 nM, lestaurtinib (30, 100, and 300 nM; 1 hour) suppresses the phosphorylation of JAK2, STAT5, and STAT3 [2]. | |
| ln Vivo | Lestaurtinib (20 mg/kg; subcutaneous injection; once daily on Saturday and Sunday and twice on Monday through Friday) significantly inhibits the growth of tumors in vivo [3]. | |
| Cell Assay |
Cell viability assay[1] Cell Types: KMH2, CAL62, THJ-21T Cell Tested Concentrations: 0.01-10 µM Incubation Duration: 72 hrs (hours) Experimental Results: demonstrated good growth inhibitory activity, the IC50 of KMH2, CAL62 and THJ were 0.21 and 0.41 respectively and 2.35 µM for -21T cells, respectively. Cell proliferation assay[1] Cell Types: WI-38, CAL62 and KMH2 Cell Tested Concentrations: 0.5 µM Incubation Duration: 24 hrs (hours) Experimental Results: ATC cell proliferation was inhibited. Cell cycle analysis [1] Cell Types: CAL62 and KMH2 cells Tested Concentrations: 4 μM Incubation Duration: 24 h Experimental Results: Resulting in an increase in the number of cells in the G2/M phase and a decrease in the number of cells in the G1/M phase in the G0 and S phases (KMH2 cells are better than CAL62 cells more significant). Western Blot Analysis[1] Cell Types: CAL62 Cell Tested Concentrations: 0.125-4 µM Incubation Duration: 24 hrs (hours) Experimental Results: pSTAT5 was diminished in a concentration-dependent manner, with complete loss of pSTAT5 expression at 4 µM. Apoptosis analysis[2] Cell Types: L-428, L-12 |
|
| Animal Protocol |
Animal/Disease Models: 4weeks old athymic nu/nu (nude) mice (SY5Y-TrkB xenograft model) [3]. Doses: 20 mg/kg Route of Administration: subcutaneous injection; twice (two times) daily (Monday to Friday) and one time/day (Saturday and Sunday); 3 weeks. Experimental Results: Dramatically slowed growth of SY5Y-TrkB xenografts. |
|
| References |
[1]. Lestaurtinib is a potent inhibitor of anaplastic thyroid cancer cell line models. PLoS One. 2018 Nov 12;13(11):e0207152. [2]. Lestaurtinib inhibition of the Jak/STAT signaling pathway in hodgkin lymphoma inhibits proliferation and induces apoptosis. PLoS One. 2011 Apr 20;6(4):e18856. [3]. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma. Clin Cancer Res. 2010 Mar 1;16(5):1478-85. [4]. A FLT3-targeted tyrosine kinase inhibitor is cytotoxic to leukemia cells in vitro and in vivo. Blood. 2002 Jun 1;99(11):3885-91. [5]. Lestaurtinib, a multitargeted tyrosine kinase inhibitor: from bench to bedside. Expert Opin Investig Drugs. 2010 Mar;19(3):427-36. [6]. Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders. Blood. 2008 Jun 15;111(12):5663-71. |
|
| Additional Infomation |
LSM-1231 is an indolocarbazole. Lestaurtinib is an orally bioavailable indolocarbazole derivative with antineoplastic properties. Lestaurtinib inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3. (NCI05) Drug Indication Investigated for use/treatment in pancreatic cancer, prostate cancer, and leukemia (myeloid). Mechanism of Action Lestaurtinib inhibits autophosphorylation of FMS-like tyrosine kinase 3 (FLT3), resulting in inhibition of FLT3 activity and induction of apoptosis in tumor cells that overexpress FLT3. |
Solubility Data
| Solubility (In Vitro) | DMSO : ~50 mg/mL (~113.78 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (5.69 mM) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.73 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (4.73 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 20.8 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. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2755 mL | 11.3776 mL | 22.7552 mL | |
| 5 mM | 0.4551 mL | 2.2755 mL | 4.5510 mL | |
| 10 mM | 0.2276 mL | 1.1378 mL | 2.2755 mL |