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Purity: ≥98%
Filanesib (formerly also known as ARRY-520) is a novel, potent and synthetic small molecule inhibitor of kinesin spindle protein (KSP) with anticancer activity. It inhibits KSP with IC50 of 6 nM. Kinesin spindle protein (KSP) is a microtubule-associated motor protein that is overexpressed in a number of cancers and may be used as an anti-tumor target. KSP is necessary for the progression of the cell cycle. In acute myeloid leukemia cell lines that express high levels of KSP, filanesib blocked cell cycle progression, resulting in apoptosis. The response to ARRY-520 appeared to be unaffected by p53 knockdown, XIAP overexpression, or caspase-8 mutation, indicating that these factors are not connected to the response. ARRY-520 induced mitotic arrest in HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, but in HL-60Bcl-2 cells, cell death was attenuated, indicating that the mitochondrial pathway is involved in the execution of the apoptotic program. In HL-60Bcl-2 cells, ABT-737's inhibition of Bcl-2 was therefore synergistic with ARRY-520. Moreover, in HL-60 cells, ARRY-520 raised Bim protein levels before caspase activation. ARRY-520 markedly reduced the growth of xenograft tumors in SCID mice and inhibited AML blast formation, but not normal colony formation. These results indicate that KSP plays a crucial role in the proliferation of leukemic progenitor cells. These findings show that ARRY-520 has the ability to completely eliminate AML progenitor cells by potently inducing cell cycle block and subsequent death in leukemic cells via the mitochondrial pathway.
| Targets |
KSP (EC50 = 6 nM)
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|---|---|
| ln Vitro |
Finerenone inhibits the proliferation of aldosterone-induced smooth muscle cells (SMC) and stops the apoptosis of aldosterone-induced endothelial cells (EC) in vitro. Finerenone causes an increase in endothelial healing and a decrease in the formation of neointima in injured vessels by dramatically lowering EC apoptosis while concurrently attenuating SMC proliferation.[2]
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| ln Vivo |
Finerenone reduces superoxide anion levels because of an increase in SOD activity and improves endothelial dysfunction by increasing NO bioavailability. This is linked to a decrease in albuminuria and an increase in renal SOD activity.[1]
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| Cell Assay |
For the purpose of measuring cell proliferation and apoptosis, cells are serum-starved for 24 hours before being incubated with aldosterone with or without finerenone. Cells are preincubated with finerenone or vehicle for 30 minutes prior to the addition of aldosterone.
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| Animal Protocol |
Tumor xenografts placed subcutaneously are allowed to expand to a volume of 250–350 mm3. Depending on the size of their tumors, the mice are randomly assigned to groups of three to four and given a single intraperitoneal dose of filanesib (ARRY-520). The mice are put to sleep by CO2 inhalation at different intervals following the drug's administration, and the tumors are removed and put in 10% neutral buffered formalin. The tumors that have been fixed in formalin are processed and paraffin embedded using standard protocols. Tumor sections stained with α-tubulin are used to analyze spindle morphology, and TUNEL stain is used to analyze apoptosis. Algorithms developed in ImagePro software are used to analyze the count of TUNEL positive (apoptotic) cells and monopolar/abnormal spindles in three ×40 fields from each sample.
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| References | |
| Additional Infomation |
Filanesib is a potent Kinesin Spindle Protein (KSP) inhibitor that caused marked tumor regression in preclinical models of human solid tumors and human leukemias, often leading to durable responses.
Filanesib is a synthetic, small molecule targeting the kinesin spindle protein (KSP) with potential antineoplastic activity. Filanesib specifically inhibits KSP (kinesin-5 or Eg5), resulting in activation of the spindle assembly checkpoint, induction of cell cycle arrest during the mitotic phase, and consequently cell death in tumor cells that are actively dividing. Because KSP is not involved in postmitotic processes, such as neuronal transport, this agent does not cause the peripheral neuropathy that is often associated with tubulin-targeting agents. KSP is an ATP-dependent microtubule motor protein that is essential for the formation of bipolar spindles and the proper segregation of sister chromatids during mitosis. Drug Indication Investigated for use/treatment in cancer/tumors (unspecified). Mechanism of Action KSP has been identified as an attractive drug target against cancer. Cancer results when normal cellular processes go awry and lead to a massive, uncontrolled cell division, proliferation, and growth. Inhibitors of KSP cause mitotic arrest by preventing the formation of bipolar spindle. The monopolar spindle thus prevents the separation of centrosomes, organizes the microtubules from a single locus in the cell, and aligns the chromosomes around this locus. This compound is a highly potent KSP inhibitor that demonstrates subnanomolar potency in both enzymatic and cellular assays and causes mitotic arrest, leading to cell death or apoptosis of the immensely proliferating cancer cells. Pharmacodynamics This compound is a highly potent KSP inhibitor that demonstrates subnanomolar potency in both enzymatic and cellular assays and causes mitotic arrest, leading to cell death or apoptosis of the immensely proliferating cancer cells. |
| Molecular Formula |
C20H22N4O2F2S
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|---|---|
| Molecular Weight |
420.47608
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| Exact Mass |
420.143
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| Elemental Analysis |
C, 57.13; H, 5.27; F, 9.04; N, 13.32; O, 7.61; S, 7.6
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| CAS # |
885060-09-3
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| Related CAS # |
(R)-Filanesib;885060-08-2;Filanesib TFA;1781834-99-8
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| PubChem CID |
44224257
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| Appearance |
white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
511.3±60.0 °C at 760 mmHg
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| Flash Point |
263.0±32.9 °C
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| Vapour Pressure |
0.0±1.3 mmHg at 25°C
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| Index of Refraction |
1.604
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| LogP |
3.27
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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-FQEVSTJZSA-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-/m0/s1
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| Chemical Name |
(2S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3-carboxamide
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| Synonyms |
Filanesib; ARRY520; ARRY 520; ARRY-520
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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: ~76 mg/mL (~200.8 mM)
Ethanol: ~10 mg/mL (~26.4 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.95 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 (5.95 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.95 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 5%DMSO+40%PEG300+5%Tween80+50%ddH2O: 3.8mg/ml |
| 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 |
| NCT01372540 | Completed | Drug: Carfilzomib Drug: Filanesib |
Recurrent Plasma Cell Myeloma Plasma Cell Leukemia |
M.D. Anderson Cancer Center | February 24, 2012 | Phase 1 |
| NCT02384083 | Completed | Drug: Filanesib, pomalidomide and dexamethasone |
Multiple Myeloma | PETHEMA Foundation | September 2015 | Phase 1 Phase 2 |
| NCT00637052 | Completed | Drug: ARRY-520, KSP(Eg5) inhibitor; intravenous |
Advanced MDS Acute Myeloid Leukemia |
Pfizer | March 18, 2008 | Phase 1 Phase 2 |
 ARRY-520 induces dose- and time-dependent cell death in acute leukemic cells.
ARRY-520-induced cell death is independent of XIAP levels and activation of the extrinsic apoptotic pathway.
ARRY-520 greatly inhibits the colony formation capacity of BM from patients with AML.Leukemia.2009 Oct;23(10):1755-62. |
|---|
 ARRY-520 induces G2M cell cycle block prior to cell death. ARRY-520 induces primarily G2M cell death.
KSP is highly expressed in acute leukemia cell lines and in most samples of AML blasts.Leukemia.2009 Oct;23(10):1755-62. |
 ARRY-520-induced cell death is mediated via the mitochondrial apoptotic pathway.
ARRY-520 significantly inhibits tumor growth in HL60 (A) and MV4-11 (B) xenografts of SCID mice.Leukemia.2009 Oct;23(10):1755-62. |
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