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].
Clinical trial: No clinical data are available currently.
Reference:
[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.