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(R)-Filanesib, the R-enantiomer of ARRY-520, is a novel and potent kinesin spindle protein (KSP) inhibitor (IC50 = 6 nM) with anticancer activity.
| ln Vitro |
Filanesib (ARRY520; ARRY-520) continues to function in cell lines resistant to multiple drugs. Filanesib (ARRY-520) has EC50s of 3.7, 14, and 4.2 nM for inhibiting the proliferation of HCT-15, NCI/ADR-RES, and K562/ADR cells, respectively. Most cells in mitosis are blocked by filanesib (ARRY-520) (10 nM) with the monopolar spindle structure characteristic of KSP inhibition[1]. In four cells, increased phosphorylation of histone H3 (pHH3) and accumulation of cyclin B1 indicate that filanesib (ARRY-520) (10 nM) induces mitotic arrest[2]. The cytotoxic effects of Paclitaxel and Filanesib (ARRY-520) on Type I and II cells are identical. For Type II EOC cells, the GI50 at 48 hours is 0.0015 μM for ARRY-520. The GI50 for ARRY-520 at 48 hours is greater than 3 μM in Type I EOC cells[3]. In OCI-AML3 cells, filanesib (ARRY-520) at 1 nM causes a substantial G2M cell cycle block within 24 hours[4].
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| ln Vivo |
Filanesib (ARRY520; ARRY-520) (10, 15, 20, 30 mg/kg, i.p.) is more effective than paclitaxel in mice with subcutaneous HT-29, HCT-116, MDA-MB-231, and A2780 xenografts, as well as active in UISO-BCA-1 xenografts. In both the DU145 prostate xenograft model and the androgen receptor-negative PC-3 prostate cancer xenograft model, ARRY-520 outperforms docetaxel[1]. Tumor xenografts from RPMI 8226 are especially responsive to low dosages of ARRY-520 (12.5 mg/kg, i.p.)[2]. In HL60 and MV4-11 xenografts of SCID mice, ARRY-520 dramatically inhibits tumor growth at doses of 27 mg/kg and 20 mg/kg, respectively[4].
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| Cell Assay |
Filanesib (ARRY-520) is applied to exponentially growing cells (0.4×106/mL) for a maximum of 48 hours. For a maximum of 96 hours, Filanesib (ARRY-520), ABT-737, or both are incubated with HL-60 and HL-60Bcl-2 cells (0.4×106/mL). The control agent in this case is DMSO. The Annexin-V-FLUOS Staining Kit is used in flow cytometry measurements of phosphatidyl serine to estimate apoptosis. Simultaneous assessment of membrane integrity is conducted with 7-amino-actinomycin D (7-AAD). For one hour at 37°C, cells are loaded with CMXRos (300 nM) and MitoTracker Green (500 nM) in order to measure changes in the mitochondrial membrane potential (MMP). Next, CMXRos retention is measured and the loss of MMP is evaluated while simultaneously correcting for mitochondrial mass.
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| Animal Protocol |
Tumor xenografts placed subcutaneously are permitted to expand to a volume of 250–350 mm3. Based on the size of their tumors, the mice are randomly assigned to groups of three to four, and each group receives a single intraperitoneal dose of filanesib (ARRY-520). The mice are put to death by CO2 inhalation at different intervals following the drug's administration, and the tumors are removed and put in 10% neutral buffered formalin. Standard procedures are followed to process and paraffin embed the formalin-fixed tumors. TUNEL stain is used to analyze apoptosis, and α-tubulin staining is used to analyze spindle morphology in tumor sections. For every sample, three ×40 fields are counted to identify monopolar/abnormal spindles and TUNEL positive (apoptotic) cells, which are then analyzed using algorithms built into the ImagePro software.
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| References |
| Molecular Formula |
C20H22F2N4O2S
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|---|---|
| Molecular Weight |
420.476089954376
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| Exact Mass |
420.143
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| CAS # |
885060-08-2
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| Related CAS # |
Filanesib;885060-09-3
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| PubChem CID |
46189838
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| Appearance |
White to off-white solid
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| LogP |
3.954
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
605
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| Defined Atom Stereocenter Count |
1
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| SMILES |
C([C@@]1(SC(C2C=C(F)C=CC=2F)=NN1C(=O)N(C)OC)C1C=CC=CC=1)CCN
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| InChi Key |
LLXISKGBWFTGEI-HXUWFJFHSA-N
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| InChi Code |
InChI=1S/C20H22F2N4O2S/c1-25(28-2)19(27)26-20(11-6-12-23,14-7-4-3-5-8-14)29-18(24-26)16-13-15(21)9-10-17(16)22/h3-5,7-10,13H,6,11-12,23H2,1-2H3/t20-/m1/s1
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| Chemical Name |
(2R)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3-carboxamide
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| Synonyms |
(R)-ARRY-520; (R)-Filanesib
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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: ≥ 100 mg/mL (~237.8 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3.75 mg/mL (8.92 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 37.5 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. Solubility in Formulation 2: ≥ 3.75 mg/mL (8.92 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 37.5 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 | 2.3782 mL | 11.8912 mL | 23.7823 mL | |
| 5 mM | 0.4756 mL | 2.3782 mL | 4.7565 mL | |
| 10 mM | 0.2378 mL | 1.1891 mL | 2.3782 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT02384083 | Completed | Drug: Filanesib, pomalidomide and dexamethasone |
Multiple Myeloma | PETHEMA Foundation | September 2015 | Phase 1 Phase 2 |
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