Filanesib TFA | ARRY-520 | 1781834-99-8 | KSP inhibitor

MedKoo Cat#: 206982 | Name: Filanesib TFA

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Description:

WARNING: This product is for research use only, not for human or veterinary use.

Filanesib, also known as ARRY-520, is a synthetic, small molecule targeting the kinesin spindle protein (KSP) with potential antineoplastic activity. KSP inhibitor ARRY-520 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.

Chemical Structure

Filanesib TFA

CAS#1781834-99-8 (TFA)

Theoretical Analysis

MedKoo Cat#: 206982

Name: Filanesib TFA

CAS#: 1781834-99-8 (TFA)

Chemical Formula: C22H23F5N4O4S

Exact Mass: 0.0000

Molecular Weight: 534.50

Elemental Analysis: C, 49.44; H, 4.34; F, 17.77; N, 10.48; O, 11.97; S, 6.00

Price and Availability

Size	Price	Availability	Quantity
10mg	USD 600.00	2 Weeks

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Related CAS #

885060-09-3 (free base) 1781834-99-8 (TFA) 885060-08-2 (R-isomer) 1385020-40-5 (HCl)

Synonym

Filanesib TFA, Filanesib trifluoroacetic acid; ARRY-520 TFA; ARRY520 TFA; ARRY 520 TFA;

IUPAC/Chemical Name

(S)-2-(3-aminopropyl)-5-(2,5-difluorophenyl)-N-methoxy-N-methyl-2-phenyl-1,3,4-thiadiazole-3(2H)-carboxamide 2,2,2-trifluoroacetate

InChi Key

CIJUJPVFECBUKG-BDQAORGHSA-N

InChi Code

InChI=1S/C20H22F2N4O2S.C2HF3O2/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;3-2(4,5)1(6)7/h3-5,7-10,13H,6,11-12,23H2,1-2H3;(H,6,7)/t20-;/m0./s1

SMILES Code

FC1=CC=C(F)C=C1C2=NN(C(N(C)OC)=O)[C@](CCCN)([C@]3=CC=CC=C3)S2.FC(F)(F)C(O)=O

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.03.00

More Info

Product Data

Product Data

Instruction

View handling instruction

Biological target:

Filanesib TFA (ARRY-520 TFA) is a selective kinesin spindle protein (KSP) inhibitor, with an IC50 of 6 nM for human KSP.

In vitro activity:

Inhibition of KSP by ARRY-520 blocked cell cycle progression, leading to apoptosis in acute myeloid leukemia cell lines that express high levels of KSP. Knockdown of p53, overexpression of XIAP and mutation in caspase-8 did not significantly affect sensitivity to ARRY-520, suggesting that the response is independent of p53, XIAP and the extrinsic apoptotic pathway. Although ARRY-520 induced mitotic arrest in both HL-60 and Bcl-2-overexpressing HL-60Bcl-2 cells, cell death was blunted in HL-60Bcl-2 cells, suggesting that the apoptotic program is executed through the mitochondrial pathway. Furthermore, ARRY-520 increased Bim protein levels prior to caspase activation in HL-60 cells. Reference: Leukemia. 2009 Oct;23(10):1755-62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593228/

In vivo activity:

SCID mice implanted with HL-60 cells were treated with ARRY-520 to evaluate its effect in vivo. As shown in Figure 8A, ARRY-520 greatly decreased tumor volumes and all 5 mice showed complete responses (CR) on day 15. Although tumor growth was significantly inhibited during ARRY-520 treatment and became undetectable shortly after the treatment, tumors eventually outgrew suggesting that prolonged/repeated treatment is required to achieve better outcome. Reference: Leukemia. 2009 Oct;23(10):1755-62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593228/

	Solvent	mg/mL	mM
Solubility
	DMSO	31.5	59.01
	Ethanol	31.5	59.01

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 534.50 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

1. Carter BZ, Mak DH, Woessner R, Gross S, Schober WD, Estrov Z, Kantarjian H, Andreeff M. 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. doi: 10.1038/leu.2009.101. Epub 2009 May 21. PMID: 19458629; PMCID: PMC3593228. 2. Woessner R, Tunquist B, Lemieux C, Chlipala E, Jackinsky S, Dewolf W Jr, Voegtli W, Cox A, Rana S, Lee P, Walker D. ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res. 2009 Nov;29(11):4373-80. PMID: 20032381.

In vitro protocol:

In vivo protocol:

1: Milic B, Chakraborty A, Han K, Bassik MC, Block SM. KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics. Proc Natl Acad Sci U S A. 2018 May 15;115(20):E4613-E4622. doi: 10.1073/pnas.1801242115. Epub 2018 Apr 27. PubMed PMID: 29703754; PubMed Central PMCID: PMC5960320. 2: Hernández-García S, San-Segundo L, González-Méndez L, Corchete LA, Misiewicz-Krzeminska I, Martín-Sánchez M, López-Iglesias AA, Algarín EM, Mogollón P, Díaz-Tejedor A, Paíno T, Tunquist B, Mateos MV, Gutiérrez NC, Díaz-Rodriguez E, Garayoa M, Ocio EM. The kinesin spindle protein inhibitor filanesib enhances the activity of pomalidomide and dexamethasone in multiple myeloma. Haematologica. 2017 Dec;102(12):2113-2124. doi: 10.3324/haematol.2017.168666. Epub 2017 Aug 31. PubMed PMID: 28860344; PubMed Central PMCID: PMC5709111. 3: Shah JJ, Kaufman JL, Zonder JA, Cohen AD, Bensinger WI, Hilder BW, Rush SA, Walker DH, Tunquist BJ, Litwiler KS, Ptaszynski M, Orlowski RZ, Lonial S. A Phase 1 and 2 study of Filanesib alone and in combination with low-dose dexamethasone in relapsed/refractory multiple myeloma. Cancer. 2017 Dec 1;123(23):4617-4630. doi: 10.1002/cncr.30892. Epub 2017 Aug 17. PubMed PMID: 28817190; PubMed Central PMCID: PMC5856158. 4: D'Agostino M, Salvini M, Palumbo A, Larocca A, Gay F. Novel investigational drugs active as single agents in multiple myeloma. Expert Opin Investig Drugs. 2017 Jun;26(6):699-711. doi: 10.1080/13543784.2017.1324571. Epub 2017 May 8. Review. PubMed PMID: 28448171. 5: Chen GY, Kang YJ, Gayek AS, Youyen W, Tüzel E, Ohi R, Hancock WO. Eg5 Inhibitors Have Contrasting Effects on Microtubule Stability and Metaphase Spindle Integrity. ACS Chem Biol. 2017 Apr 21;12(4):1038-1046. doi: 10.1021/acschembio.6b01040. Epub 2017 Feb 22. PubMed PMID: 28165699; PubMed Central PMCID: PMC5515541. 6: Zhang K, Desai A, Zeng D, Gong T, Lu P, Wang M. Magic year for multiple myeloma therapeutics: Key takeaways from the ASH 2015 annual meeting. Oncotarget. 2017 Feb 7;8(6):10748-10759. doi: 10.18632/oncotarget.13314. Review. PubMed PMID: 27863374; PubMed Central PMCID: PMC5354697. 7: Chari A, Htut M, Zonder JA, Fay JW, Jakubowiak AJ, Levy JB, Lau K, Burt SM, Tunquist BJ, Hilder BW, Rush SA, Walker DH, Ptaszynski M, Kaufman JL. A phase 1 dose-escalation study of filanesib plus bortezomib and dexamethasone in patients with recurrent/refractory multiple myeloma. Cancer. 2016 Nov 15;122(21):3327-3335. doi: 10.1002/cncr.30174. Epub 2016 Jul 19. PubMed PMID: 27433944. 8: Norris EJ, DeStephanis D, Tunquist B, Usmani S, Ganapathi R, Ganapathi M. Cytotoxic efficacy of filanesib and melphalan combination is governed by sequence of treatment in human myeloma cells. Blood Cancer J. 2016 Oct 7;6(10):e480. doi: 10.1038/bcj.2016.92. PubMed PMID: 27716742; PubMed Central PMCID: PMC5098264. 9: Rajan AM, Kumar S. New investigational drugs with single-agent activity in multiple myeloma. Blood Cancer J. 2016 Jul 29;6(7):e451. doi: 10.1038/bcj.2016.53. Review. PubMed PMID: 27471867; PubMed Central PMCID: PMC5030378. 10: Naymagon L, Abdul-Hay M. Novel agents in the treatment of multiple myeloma: a review about the future. J Hematol Oncol. 2016 Jun 30;9(1):52. doi: 10.1186/s13045-016-0282-1. Review. PubMed PMID: 27363832; PubMed Central PMCID: PMC4929712. 11: Ito S. [Novel agents in multiple myeloma treatment]. Rinsho Ketsueki. 2015 Oct;56(10):2066-73. doi: 10.11406/rinketsu.56.2066. Japanese. PubMed PMID: 26458446. 12: LoRusso PM, Goncalves PH, Casetta L, Carter JA, Litwiler K, Roseberry D, Rush S, Schreiber J, Simmons HM, Ptaszynski M, Sausville EA. First-in-human phase 1 study of filanesib (ARRY-520), a kinesin spindle protein inhibitor, in patients with advanced solid tumors. Invest New Drugs. 2015 Apr;33(2):440-9. doi: 10.1007/s10637-015-0211-0. Epub 2015 Feb 17. PubMed PMID: 25684345. 13: Ocio EM, Mitsiades CS, Orlowski RZ, Anderson KC. Future agents and treatment directions in multiple myeloma. Expert Rev Hematol. 2014 Feb;7(1):127-41. doi: 10.1586/17474086.2014.858595. Epub 2013 Dec 18. Review. PubMed PMID: 24350987; PubMed Central PMCID: PMC4157182. 14: Owens B. Kinesin inhibitor marches toward first-in-class pivotal trial. Nat Med. 2013 Dec;19(12):1550. doi: 10.1038/nm1213-1550a. PubMed PMID: 24309639. 15: Ocio EM, Richardson PG, Rajkumar SV, Palumbo A, Mateos MV, Orlowski R, Kumar S, Usmani S, Roodman D, Niesvizky R, Einsele H, Anderson KC, Dimopoulos MA, Avet-Loiseau H, Mellqvist UH, Turesson I, Merlini G, Schots R, McCarthy P, Bergsagel L, Chim CS, Lahuerta JJ, Shah J, Reiman A, Mikhael J, Zweegman S, Lonial S, Comenzo R, Chng WJ, Moreau P, Sonneveld P, Ludwig H, Durie BG, Miguel JF. New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG). Leukemia. 2014 Mar;28(3):525-42. doi: 10.1038/leu.2013.350. Epub 2013 Nov 20. Review. PubMed PMID: 24253022; PubMed Central PMCID: PMC4143389. 16: Lee HC, Shah JJ, Orlowski RZ. Novel approaches to treatment of double-refractory multiple myeloma. Am Soc Clin Oncol Educ Book. 2013. doi: 10.1200/EdBook_AM.2013.33.e302. Review. PubMed PMID: 23714530; PubMed Central PMCID: PMC3762449. 17: Khoury HJ, Garcia-Manero G, Borthakur G, Kadia T, Foudray MC, Arellano M, Langston A, Bethelmie-Bryan B, Rush S, Litwiler K, Karan S, Simmons H, Marcus AI, Ptaszynski M, Kantarjian H. A phase 1 dose-escalation study of ARRY-520, a kinesin spindle protein inhibitor, in patients with advanced myeloid leukemias. Cancer. 2012 Jul 15;118(14):3556-64. doi: 10.1002/cncr.26664. Epub 2011 Dec 2. PubMed PMID: 22139909; PubMed Central PMCID: PMC4984525. 18: Tunquist BJ, Woessner RD, Walker DH. 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. doi: 10.1158/1535-7163.MCT-10-0033. Epub 2010 Jun 22. PubMed PMID: 20571074. 19: Woessner R, Tunquist B, Lemieux C, Chlipala E, Jackinsky S, Dewolf W Jr, Voegtli W, Cox A, Rana S, Lee P, Walker D. ARRY-520, a novel KSP inhibitor with potent activity in hematological and taxane-resistant tumor models. Anticancer Res. 2009 Nov;29(11):4373-80. PubMed PMID: 20032381. 20: Kim KH, Xie Y, Tytler EM, Woessner R, Mor G, Alvero AB. KSP inhibitor ARRY-520 as a substitute for Paclitaxel in Type I ovarian cancer cells. J Transl Med. 2009 Jul 20;7:63. doi: 10.1186/1479-5876-7-63. PubMed PMID: 19619321; PubMed Central PMCID: PMC2719595.