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CYT997 (also called Lexibulin; CYT-997; CYT 997) is a potent VDA-vascular disrupting agent and also a potent microtubule polymerization/mitotic inhibitor with potential anticancer activity. It inhibits the proliferation of various cancer cells with IC50s of 10-100 nM. It belongs to the so called microtubule-destablizer which inhibits the dynamic instability and polymerization of tubulin.
Physicochemical Properties
| Molecular Formula | C24H30N6O2 | |
| Molecular Weight | 434.53 | |
| Exact Mass | 434.243 | |
| CAS # | 917111-44-5 | |
| Related CAS # | Lexibulin dihydrochloride;917111-49-0 | |
| PubChem CID | 11351021 | |
| Appearance | White to off-white solid powder | |
| Density | 1.2±0.1 g/cm3 | |
| Boiling Point | 557.7±50.0 °C at 760 mmHg | |
| Flash Point | 291.1±30.1 °C | |
| Vapour Pressure | 0.0±1.5 mmHg at 25°C | |
| Index of Refraction | 1.610 | |
| LogP | 4.14 | |
| Hydrogen Bond Donor Count | 3 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 9 | |
| Heavy Atom Count | 32 | |
| Complexity | 565 | |
| Defined Atom Stereocenter Count | 1 | |
| SMILES | CCC[C@@H](C1=CN=CC=C1)NC2=NC(=NC=C2C)C3=CC(=C(C=C3)NC(=O)NCC)OC |
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| InChi Key | MTJHLONVHHPNSI-IBGZPJMESA-N | |
| InChi Code | InChI=1S/C24H30N6O2/c1-5-8-19(18-9-7-12-25-15-18)28-22-16(3)14-27-23(30-22)17-10-11-20(21(13-17)32-4)29-24(31)26-6-2/h7,9-15,19H,5-6,8H2,1-4H3,(H2,26,29,31)(H,27,28,30)/t19-/m0/s1 | |
| Chemical Name | (S)-1-ethyl-3-(2-methoxy-4-(5-methyl-4-((1-(pyridin-3-yl)butyl)amino)pyrimidin-2-yl)phenyl)urea | |
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| 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 |
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| 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
| ln Vitro | Using the standard turbidimetric assay for tubulin polymerization, lexibulin (CYT-997) inhibits tubulin polymerization in vitro with an IC50 of approximately 3 μmol/L (compared with the half-maximal inhibitory concentration of 2 μmol/L for colchicine under identical conditions). Moreover, lexibulin can reversibly damage cells' microtubule networks, as demonstrated by fluorescence microscopy. Therefore, applying Lexibulin (1 μM) to A549 cells caused a rapid reorganization of microtubules, including the disintegration of the preexisting microtubule network and the build-up of tubulin in plaques within some cells' cytoplasm. Major changes in cell morphology, such as rounding of the cell and loss of adhesion, are visible after 24 hours. After receiving Lexibulin for an hour, the effects wear off quickly and the cells quickly revert to their original microtubule architecture. When considered collectively, the data suggest that lexibulin is a member of the class of anticancer drugs that damage tubulin-containing structures instead of stabilizing them. At 15 and 24 hours, respectively, cells treated with vehicle showed 15% and 19% of cells in G2-M phase; at the same time points, cells treated with 1 μM Lexibulin had 38% and 43% of cells in G2-M. Additionally, only 66% of all cells are in the G1, S, and G2-M phases 24 hours after Lexibulin treatment, which implies that cells blocked at the G2-M boundary are most likely driven towards apoptosis and cell death rather than exiting back to G1, as would be the case in a normal cell cycle[1]. Lexibulin potently inhibits proliferation, induces cell cycle arrest, and most importantly, causes apoptosis of both primary MM cells and human myeloma cell lines (HMCLs), all of which are consistent with the disruption of cellular tubulin[2]. | ||
| ln Vivo | Oral administration of Lexibulin (CYT-997) is started 13 days following cell implantation in a xenograft model utilizing the human prostate cancer cell line PC3, at which point palpable tumors were visible. With Lexibulin (CYT-997), there was a dosage-dependent reduction of tumor development that was comparable to parenterally administered paclitaxel at the highest dose. Blood flow in liver metastases was evidently reduced by a single dosage of Lexibulin (CYT-997) (7.5 mg/kg ip), and this reduction persisted for six hours after the dose[1]. Treatment with lexibulin (CYT-997) (15 mg/kg/day) prolongs survival in a mouse model of aggressive systemic myelomatosis significantly[2]. | ||
| Animal Protocol |
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| References |
[1]. CYT997: a novel orally active tubulin polymerization inhibitor with potent cytotoxic and vascular disrupting activity in vitro and in vivo. Mol Cancer Ther. 2009 Nov;8(11):3036-45. [2]. CYT997 causes apoptosis in human multiple myeloma. Invest New Drugs. 2011 Apr;29(2):232-8. [3]. Ya Cao, wt al. Mitochondrial ROS Accumulation Inhibiting JAK2/STAT3 Pathway Is a Critical Modulator of CYT997-induced Autophagy and Apoptosis in Gastric Cancer. J Exp Clin Cancer Res. 2020 Jun 23;39(1):119. |
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| Additional Infomation |
1-ethyl-3-[2-methoxy-4-[5-methyl-4-[[(1S)-1-(3-pyridinyl)butyl]amino]-2-pyrimidinyl]phenyl]urea is a member of ureas. CYT997 is an orally available vascular argeting and cytotoxic agent that has proven effective in animal models of a wide range of tumour types including breast, prostate and colon, as well as some leukemias. Lexibulin is an orally bioavailable small-molecule with tubulin-inhibiting, vascular-disrupting, and potential antineoplastic activities. Lexibulin inhibits tubulin polymerization in tumor blood vessel endothelial cells and tumor cells, blocking the formation of the mitotic spindle and leading to cell cycle arrest at the G2/M phase; this may result in disruption of the tumor vasculature and tumor blood flow, and tumor cell death. Drug Indication Investigated for use/treatment in solid tumors. Mechanism of Action CYT997 is a vascular disrupting agent and a tubulin inhibitor for various cancers. The essential role of microtubules in cell division and the capacity of drugs that interact with the protein subunits of microtubules (α- and β-tubulin) to interfere with the cell cycle, have made tubulin a highly successful target for the development of therapeutic drugs, such as anti-cancer drugs and vascular disrupting agents. |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.75 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 25.0 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 2: ≥ 2.5 mg/mL (5.75 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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3013 mL | 11.5067 mL | 23.0134 mL | |
| 5 mM | 0.4603 mL | 2.3013 mL | 4.6027 mL | |
| 10 mM | 0.2301 mL | 1.1507 mL | 2.3013 mL |