The erythroblastosis virus E26 transforming sequences (ETS) family of transcription factors consists of a highly conserved group of genes that play important roles in cellular proliferation, differentiation, migration and invasion. ERG and ETV1 are the most commonly translocated ETS proteins, YK-4-279 is a small molecule antagonist of ETV1[3]. Due to its hydrophobic structure, the bioavailability of YK-4-279 is only 2%-15% when it is administered to mice by oral gavage. Intra-peritoneal administrations of 75 mg/kg YK-4-279 initially leads to a steep rise in plasma concentrations, but is substantially cleared leading to ,1 mM levels by 2 hours[4]. Exposure of LNCaP-luc-M6 cells to 1 mM YK-4-279 resulted in significantly reduced mRNA levels of several ETV1 target genes, including MMP7, MMP13, FKBP10 and GLYATL2, without affecting the expression of ETV1[3]. Maximal YK-4-279 concentrations (Cmax) of 90 and 10 μmol/L, respectively, occurred 30 minutes after i.p. or p.o. dosing. YKPO achieved an oral bioavailability of 61% to 73% and peak serum concentration 6.7-fold higher than the half-maximal inhibitory dose observed in vitro (IC50, 1 μmol/L)[5]. The combination of low-dose docetaxel and YK-4-279 synergistically inhibited growth and induced apoptosis in human prostate cancer cells. The combination also more efficiently suppressed the migration and invasion of LNCaP and PC-3 cells. The combination of low-dose docetaxel and YK-4-279 caused a stronger decrease in the levels of ETV1, AR, PSA, p-STAT3,survivin, Bcl-2, and p-Akt in LNCaP cells and of p-Akt, Bcl-2, and p-STAT3 in PC-3 cells compared with either drug alone[6].
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