Chemical Properties
A crystalline solid
Uses
An oncogenic fusion protein found in Ewing's sarcoma, a family of undifferentiated tumors which occur throughout the body. The binding of ES-FLI1 to RNA helicase A (RHA) promotes its oncogenic function. Inhibits protein-protein interactions between ES-FLI1 and RHA. At 10 μM, YK-4-279 blocks RHA binding to ES-FLI1 and induces apoptosis of a panel of Ewing's sarcoma tumor cell lines with IC50 values ranging from 0.5 to 2 μM.1 At 1.5 mg per dose, YK-4-279 reduces the growth of Ewing's sarcoma orthotopic xenografts in mice after treatment with the inhibitor for two weeks.
Uses
YK-4-279 is a small molecule inhibitor of EWS-FLI1 protein, and has been shown to disrupt the mitotic progression of neuroblastoma cells, and potentially other cancers.
Definition
ChEBI: 4,7-dichloro-3-hydroxy-3-[2-(4-methoxyphenyl)-2-oxoethyl]-1H-indol-2-one is an aromatic ketone.
Biological Activity
yk 4-279 is an inhibitor of rna helicase a (rha) binding to the oncogenic transciption factor ews-fli1.ews-fli1 is a disordered protein that precludes standard structure-based small-molecule inhibitor design. ews-fli1 binding to rna helicase a (rha) is important for its oncogenic function.
in vitro
esft cells treated with yk-4-279 showed a dissociation of ews-fli1 from rha by 10 mm, consistent with the kd value. the ews-fli1–transfected cells showed a dose-dependent decrease in promoter activity when treated for 18 h with 3 mm and 10 mm yk-4-279. yk-4-279 was relatively specific for esft cells as compared to the nontransformed hek293 cells [1].
in vivo
the tumor growth rate of yk-4-279–treated mice bearing chp-100 was lower than that in mice having pc3 prostate tumors. the cumulative data from five independent experiments with the esft xenografts (tc71 and chp-100) show a marked overall tumor reduction in the yk-4-279–treated mice. pathological analysis of mice treated with yk-4-279 did not show any signs of toxicity, except for sterile inflammatory lesions in the abdominal cavities of mice [1].
References
[1] erkizan hv, kong y, merchant m, schlottmann s, barber-rotenberg js, yuan l, abaan od, chou th, dakshanamurthy s, brown ml, uren a, toretsky ja. a small molecule blocking oncogenic protein ews-fli1 interaction with rna helicase a inhibits growth of ewing's sarcoma. nat med. 2009;15(7):750-6.
