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ARRY-520

Names

[ CAS No. ]:
885060-09-3

[ Name ]:
ARRY-520

[Synonym ]:
UNII-8A49OSO368
(2S)-2-(3-Aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
CS-0867
1,3,4-Thiadiazole-3(2H)-carboxamide, 2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-, (2S)-
ARRY 520 trifluoroacetate
UNII: 8A49OSO368
(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide
ARRY-520
Filanesib
Filanesib [INN]

Biological Activity

[Description]:

Filanesib (ARRY-520) is a synthetic kinesin spindle protein (KSP) inhibitor with IC50 of 6 nM.

[Related Catalog]:

Signaling Pathways >> Cell Cycle/DNA Damage >> Kinesin
Signaling Pathways >> Cytoskeleton >> Kinesin
Research Areas >> Cancer

[Target]

KSP:6 nM (IC50)


[In Vitro]

Filanesib (ARRY-520) retains activity in multidrug-resistant cell lines. The EC50s of Filanesib (ARRY-520) for inhibition of proliferation of HCT-15, NCI/ADR-RES and K562/ADR cells are 3.7, 14 and 4.2 nM respectively. Filanesib (ARRY-520) (10 nM) blocks a majority of cells in mitosis with the monopolar spindle structure typical of KSP inhibition[1]. Filanesib (ARRY-520) (10 nM) induces mitotic arrest as judged by both increased phosphorylation of histone H3 (pHH3) and accumulation of cyclin B1 in four cells[2]. Filanesib (ARRY-520) and Paclitaxel exhibit the same cytotoxic effect on Type I and II cells. The GI50 at 48 h for Type II EOC cells is 0.0015 μM for ARRY-520. For Type I EOC cells, the GI50 at 48 h is > 3 μM for ARRY-520[3]. Filanesib (ARRY-520) (1 nM) induces significant G2M cell cycle block in OCI-AML3 cells at 24 hours[4].

[In Vivo]

Filanesib (ARRY-520) (10, 15, 20, 30 mg/kg, i.p.) is active in UISO-BCA-1 xenograft, and also superior to paclitaxel in mice bearing subcutaneous HT-29, HCT-116, MDA-MB-231 and A2780 xenografts. ARRY-520 is superior to docetaxel in the androgen receptor-negative prostate cancer xenograft model PC-3, and is also superior to docetaxel in the DU145 prostate xenograft model[1]. RPMI 8226 tumor xenografts are particularly sensitive to low doses of ARRY-520 (12.5 mg/kg, i.p.)[2]. ARRY-520 significantly inhibits tumor growth in HL60 and MV4-11 xenografts of SCID mice at concentrations of 27 mg/kg and 20 mg/kg, respectively[4].

[Cell Assay]

Exponentially growing cells (0.4×106/mL) are treated with Filanesib (ARRY-520) for up to 48 hours. For combination, HL-60 and HL-60Bcl-2 cells (0.4×106/mL) are incubated with Filanesib (ARRY-520), ABT-737, or both for up to 96 hours. DMSO is used as the control agent. Apoptosis is estimated by flow cytometry measurements of phosphatidyl serine with the Annexin-V-FLUOS Staining Kit. Membrane integrity is simultaneously assessed by 7-amino-actinomycin D (7-AAD). To measure changes in the mitochondrial membrane potential (MMP), cells are loaded with CMXRos (300 nM) and MitoTracker Green (500 nM) for 1 hour at 37°C. The loss of MMP is then assessed by measuring CMXRos retention while simultaneously adjusting for mitochondrial mass.

[Animal admin]

Subcutaneous tumor xenografts are allowed to grow to a volume of 250-350 mm3. The mice are randomized into groups of 3-4 based on tumor size, and are given a single dose of Filanesib (ARRY-520) i.p. At various time-points after administration of the drug, the mice are euthanized by CO2 inhalation and the tumors excised and placed in 10% neutral buffered formalin. The formalin-fixed tumors are processed and paraffin embedded by standard procedures. Spindle morphology is analyzed by staining tumor sections for α-tubulin, and apoptosis is analyzed by TUNEL stain. Monopolar/abnormal spindles and TUNEL positive (apoptotic) cells are counted in three ×40 fields from each sample, analyzed using algorithms developed in ImagePro software.

[References]

[1]. Woessner R, et al. ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res. 2009 Nov;29(11):4373-80.

[2]. Tunquist BJ, et al. Mcl-1 stability determines mitotic cell fate of human multiple myeloma tumor cells treated with the kinesin spindle protein inhibitor ARRY-520. Mol Cancer Ther. 2010 Jul;9(7):2046-56.

[3]. Kim KH, et al. KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells. J Transl Med. 2009 Jul 20;7:63.

[4]. Carter BZ, et al. Inhibition of KSP by ARRY-520 induces cell cycle block and cell death via the mitochondrial pathway in AML cells. Leukemia. 2009 Oct;23(10):1755-62.


[Related Small Molecules]

GSK-923295 | Ispinesib | Kif15-IN-1 | Monastrol | Kif15-IN-2 | Litronesib | CW-069 | K 858 | SB743921 | ARRY-520 (R enantiomer) | AZ82 | Eg5 Inhibitor V, trans-24 | EMD534085 | Paprotrain

Chemical & Physical Properties

[ Density]:
1.3±0.1 g/cm3

[ Boiling Point ]:
511.3±60.0 °C at 760 mmHg

[ Molecular Formula ]:
C20H22F2N4O2S

[ Molecular Weight ]:
420.476

[ Flash Point ]:
263.0±32.9 °C

[ Exact Mass ]:
420.143158

[ PSA ]:
96.46000

[ LogP ]:
3.27

[ Vapour Pressure ]:
0.0±1.3 mmHg at 25°C

[ Index of Refraction ]:
1.604

[ Storage condition ]:
2-8℃

Related Compounds