K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent.

K858 is a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. K858 blocked centrosome separation, activated the spindle checkpoint, and induced mitotic arrest in cells accompanied by the formation of monopolar spindles. Long-term continuous treatment of cancer cells with K858 resulted in antiproliferative effects through the induction of mitotic cell death, and polyploidization followed by senescence. K858 exhibited potent antitumor activity in xenograft models of cancer, and induced the accumulation of mitotic cells with monopolar spindles in tumor tissues.

Product information

CAS Number: 72926-24-0

Molecular Weight: 277.34

Formula: C13H15N3O2S

Synonym:

K-858

K858

K 858

Chemical Name: N-(4-acetyl-5-methyl-5-phenyl-4,5-dihydro-1,3,4-thiadiazol-2-yl)acetamide

Smiles: CC(=O)N1N=C(NC(C)=O)SC1(C)C1C=CC=CC=1

InChiKey: JEFVYQYZCAVNTP-UHFFFAOYSA-N

InChi: InChI=1S/C13H15N3O2S/c1-9(17)14-12-15-16(10(2)18)13(3,19-12)11-7-5-4-6-8-11/h4-8H,1-3H3,(H,14,15,17)

Technical Data

Appearance: Solid Power

Purity: ≥98% (or refer to the Certificate of Analysis)

Solubility: Soluble in DMSO, not in water

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis

Storage Condition: Dry, dark and -20 ^oC for 1 year or refer to the Certificate of Analysis.

Shelf Life: ≥24 months if stored properly.

Stock Solution Storage: 0 - 4 ^oC for 1 month or refer to the Certificate of Analysis.

Drug Formulation: To be determined

HS Tariff Code: 382200

How to use

In Vitro:

K858 Racemic is an ATP-uncompetitive inhibitor of Eg5 with an IC50 of 1.3 μM. K858 does not inhibit the ATPase activity of the mitotic kinesins CENP-E and MKLP1, or the conventional kinesin heavy chain even at 200 μM. K858 induces mitotic arrest and growth inhibition via the activation of the Mad2-mediated spindle checkpoint. K858 (5 μM) induces mitotic cell death in cancer cells but not in normal cells. K858 (1, 10, 100 μM) inhibits the MCF7, BT474 and SKBR3 cell lines, and only at 10 and 100 μM suppresses MDA-MB231 cell line after treatment for 24 h. K858 incereases Bax/Bcl2 RNA ratio and survivin in the four cell lines. Furthermore, the up-regulation of survivin is totally reversed by wortmannin (phosphoinositide 3-kinase AKT) in MCF7 cells.

In Vivo:

K858 (50, 150 mg/kg, p.o.) shows antitumor activity in an A2780 ovarian cancer xenograft model, also inhibits tumor grwoth in a HCT116 colon cancer xenograft model via 100 mg/kg twice a day orally for 5 days. K858 (100 mg/kg, p.o., qd ×5) displays no neurotoxic side effects in mice.

References:

1. Indorato RL, DeBonis S, Kozielski F, Garcia-Saez I, Skoufias DA. STLC-resistant cell lines as tools to classify chemically divergent Eg5 targeting agents according to their mode of action and target specificity. Biochem Pharmacol. 2013 Nov 15;86(10):1441-51. doi: 10.1016/j.bcp.2013.09.003. Epub 2013 Sep 13. PubMed PMID: 24041742.
2. Nakai R, Iida S, Takahashi T, Tsujita T, Okamoto S, Takada C, Akasaka K, Ichikawa S, Ishida H, Kusaka H, Akinaga S, Murakata C, Honda S, Nitta M, Saya H, Yamashita Y. K858, a novel inhibitor of mitotic kinesin Eg5 and antitumor agent, induces cell death in cancer cells. Cancer Res. 2009 May 1;69(9):3901-9. doi: 10.1158/0008-5472.CAN-08-4373. Epub 2009 Apr 7. PubMed PMID: 19351824.

Products are for research use only. Not for human use.