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].
Evaluate the effect of YK-4-279 on EWS-FLI1 transcriptional activity, results showed dose-dependent decrease
Nat Med. 2009 Jul;15(7):750-6
BTL695
5 µM
18 hours
To analyze the effect of YK-4-279 on TERT promoter activity. Results showed that YK-4-279 significantly downregulated the activity of the C228T TERT promoter.
Neuro Oncol. 2018 Nov 12;20(12):1584-1593
A4573 cells
3 µM YK-4-279 and 10 nM VCR
18 hours
To evaluate the apoptotic effects of YK-4-279 and VCR combination treatment, which significantly increased the proportion of apoptotic cells
Sci Signal. 2017 Oct 3;10(499):eaam8429
COS7 cells
0.35 µM (IC50 )
20 hours
Evaluate the inhibitory effect of YK-4-279 on EWS-FLI1 transcriptional activity in COS7 cells, showing an IC50 of 0.35μM.
J Med Chem. 2014 Dec 26;57(24):10290-303
BTL695
1.25 µM
24 and 48 hours
To analyze the effect of YK-4-279 on TERT mRNA expression. Results showed that YK-4-279 significantly downregulated TERT mRNA expression.
Neuro Oncol. 2018 Nov 12;20(12):1584-1593
HUVEC (static vs. flow conditions)
5 µM
24 hours
YK-4-279 reduced cell numbers and increased apoptosis under static conditions, but not under flow, suggesting flow protects ECs from apoptosis
Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26494-26502
Fibroblasts derived from diabetes mellitus wound (DMFBs)
0.3, 1, 3 µM
24 hours, 48 hours, 72 hours
To evaluate the effect of YK-4-279 on the migration ability and collagen production in DMFBs. Results showed that 1μM YK-4-279 significantly enhanced the migratory ability of DMFBs and upregulated the expression of Collagen I and α-SMA.
J Inflamm Res. 2024 Oct 16;17:7373-7388
CHP-100 cells
0.5-2 µM
3 days
Evaluate the effect of YK-4-279 on ESFT cells, results showed IC50 of 0.5-2 μM
Nat Med. 2009 Jul;15(7):750-6
A4573 cells
0.5-2 µM
3 days
Evaluate the effect of YK-4-279 on ESFT cells, results showed IC50 of 0.5-2 μM
Nat Med. 2009 Jul;15(7):750-6
TC71 cells
0.5-2 µM
3 days
Evaluate the effect of YK-4-279 on ESFT cells, results showed IC50 of 0.5-2 μM
Nat Med. 2009 Jul;15(7):750-6
GUES1 cells
8 µM
3 days
Evaluate the effect of YK-4-279 on primary ESFT cells, results showed IC50 of 8 μM
Nat Med. 2009 Jul;15(7):750-6
ES925 cells
1 µM
3 days
Evaluate the effect of YK-4-279 on primary ESFT cells, results showed IC50 of 1 μM
Nat Med. 2009 Jul;15(7):750-6
TC71 cells
0.5-2.0 µM (GI50 )
3 days
Evaluate the growth inhibitory effect of YK-4-279 on TC71 cells, showing a GI50 of 0.5-2.0μM.
J Med Chem. 2014 Dec 26;57(24):10290-303
TC32 cells
0.5-2.0 µM (GI50 )
3 days
Evaluate the growth inhibitory effect of YK-4-279 on TC32 cells, showing a GI50 of 0.5-2.0μM.
J Med Chem. 2014 Dec 26;57(24):10290-303
TC71 cells
0.88 µM (IC50 )
360 days
To investigate the resistance mechanisms of YK-4-279 in TC71 cells, results showed a 7-fold increase in IC50 value, but the resistance was not as stable as in A4573-R cells.
Mol Med Rep. 2020 Mar;21(3):1667-1675
MEL624
1 µM or 2 µM
48 hours
YK-4–279 significantly inhibited the growth and invasion of MEL624 cells and reduced MET expression.
Cancer Res. 2021 Apr 15;81(8):2071-2085
SKMEL28
1 µM or 2 µM
48 hours
YK-4–279 significantly inhibited the growth and invasion of SKMEL28 cells and reduced MET expression.
Cancer Res. 2021 Apr 15;81(8):2071-2085
A375
1 µM or 2 µM
48 hours
YK-4–279 significantly inhibited the growth and invasion of A375 cells and reduced MET expression.
Cancer Res. 2021 Apr 15;81(8):2071-2085
Human Umbilical Vein Endothelial Cells (HUVEC)
≥2.5 µM
48 hours
YK-4-279 induced HUVEC tube regression and apoptosis, with synergistic effects when combined with inflammatory cytokines
Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26494-26502
TC32 cells
3 µM YK-4-279
4-8 hours
To assess the effect of YK-4-279 on cell cycle, inducing G2-M arrest
Sci Signal. 2017 Oct 3;10(499):eaam8429
KTC-1
0.3 µM, 3 µM, 10 µM
5 days
YK-4-279 significantly inhibited thyroid cancer cell viability, with no significant difference in IC50 values between BRAF mutant and wild-type cell lines.
Front Oncol. 2021 Jun 16;11:649323
Rh41 FP-RMS cells
1 µM
5 hours
YK-4-279 reduced PAX3-FOXO1 levels on chromatin
Oncogene. 2025 Jan;44(1):19-29
Rh30 FP-RMS cells
1 µM
5 hours
YK-4-279 reduced PAX3-FOXO1 levels on chromatin
Oncogene. 2025 Jan;44(1):19-29
A4573 cells
0.54 µM (IC50 )
550 days
To investigate the resistance mechanisms of YK-4-279 in A4573 cells, results showed a nearly 30-fold increase in IC50 value in A4573-R cells.
Mol Med Rep. 2020 Mar;21(3):1667-1675
TC32 cells
900 nM
7 days
Evaluate the inhibitory effect of YK-4-279 on ESFT cell growth, results showed IC50 of 900 nM
Nat Med. 2009 Jul;15(7):750-6
Normal human fibroblasts and epithelial cell lines (NF-TERT, NF-730, RPE-1)
>20 µM (IC50 )
72 hours
Evaluate the effect of YK-4-279 on normal cells; results showed YK-4-279 had no significant inhibitory effect on normal cells
Evaluate the effect of YK-4-279 on neuroblastoma cell growth and apoptosis; results showed YK-4-279 inhibited cell growth and induced apoptosis
Cancer Lett. 2017 Sep 10;403:74-85
VM48, VM1, VM47, VM18 melanoma cells
0-50 µM
72 hours
To evaluate the effect of YK-4-279 on the viability of melanoma cells, results showed that p53/p21 non-responsive melanoma cells were more sensitive to YK-4-279.
Cancers (Basel). 2020 Oct 30;12(11):3205
FP-BH Ewing sarcoma cells
0-50 µM
72 hours
To evaluate the effect of YK-4-279 on the viability of FP-BH Ewing sarcoma cells, results showed that p53 wild-type FP-BH cells were less sensitive to YK-4-279.
Cancers (Basel). 2020 Oct 30;12(11):3205
HCT116 colon cancer cells
0-50 µM
72 hours
To evaluate the effect of YK-4-279 on the viability of HCT116 colon cancer cells, results showed that HCT116p53KO cells with p53 deletion were less sensitive to YK-4-279.
Cancers (Basel). 2020 Oct 30;12(11):3205
RKO colon cancer cells
0-50 µM
72 hours
To evaluate the effect of YK-4-279 on the viability of RKO colon cancer cells, results showed that RKOp53KO cells with p53 deletion were more sensitive to YK-4-279.
Cancers (Basel). 2020 Oct 30;12(11):3205
PC-3 cells
0.1 µM, 0.5 µM, 1.0 µM
72 hours
Evaluate the effect of YK-4-279 alone or in combination with docetaxel on the growth of PC-3 cells. Results showed that YK-4-279 alone and in combination with docetaxel inhibited the growth of PC-3 cells, with stronger effects in combination.
Int J Med Sci. 2017 Apr 7;14(4):356-366
LNCaP cells
0.1 µM, 0.5 µM, 1.0 µM
72 hours
Evaluate the effect of YK-4-279 alone or in combination with docetaxel on the growth of LNCaP cells. Results showed that YK-4-279 alone and in combination with docetaxel inhibited the growth of LNCaP cells, with stronger effects in combination.
Int J Med Sci. 2017 Apr 7;14(4):356-366
TC32 cells
3 µM
8 hours
To evaluate the effect of YK-4-279 on the RNA binding profile in the RHA-EWS-FLI1 complex, it was found that YK-4-279 altered the RNA binding profiles of both RHA and EWS-FLI1.
Nucleic Acids Res. 2015 Jan;43(2):1069-80
HeLa cells
1 nM
time-dependent
To evaluate the helicase activity of RHA, it was found that RHA unwinds double-stranded RNA into single strands in a time- and temperature-dependent manner.
Nucleic Acids Res. 2015 Jan;43(2):1069-80
YK-4-279 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice (C57BL/6J)
Neonatal murine hyaloid vessel regression model
Intravitreal injection
~1 µL, 10 μM
Single dose (injected at P5, analyzed at P7)
YK-4-279 enhanced hyaloid regression by 40%
Proc Natl Acad Sci U S A. 2020 Oct 20;117(42):26494-26502
Mice
BrafCA;Tyr-CreERT2;Ptenf/f transgenic mouse model
Continuous administration via osmotic pump
1.6 mg/kg
Continuous for 28 days
YK-4–279 significantly inhibited melanoma progression, reducing tumor thickness and invasion.
Cancer Res. 2021 Apr 15;81(8):2071-2085
Mice
BrafCA;Tyr-CreERT2;Ptenflox/flox transgenic mouse model
Intraperitoneal osmotic pump
1.6 mg/kg or 8 mg/kg
Continuous for 4 weeks
YK-4-279 significantly delayed or blocked melanoma progression. In female mice, the YK-4-279 delay group showed a significant increase in median progression-free survival time from 28 days in the MOCK group to 50 days. In male mice, 60% were progression-free in the YK-4-279 delay group.
Cancers (Basel). 2021 Dec 29;14(1):143
Mice
A4573 xenograft model
IP injection
10, 50 and 100 mg/kg
Once daily for 5 days
To evaluate the therapeutic effect of YK-4-279 on A4573 xenograft tumors, results showed significantly increased CD99 protein expression in all YK-treated groups.
Evaluate the effect of YK-4-279 on ESFT xenograft tumor growth, results showed significant inhibition of tumor growth
Nat Med. 2009 Jul;15(7):750-6
SCID/bg mice
A4573 or SKES xenograft model
Intraperitoneal injection
YK-4-279 (10-150 mg/kg) and VCR (1 mg/kg)
Once daily for 5 days on/2 days off or 7 days
To evaluate the effect of YK-4-279 and VCR combination therapy on tumor burden and survival, which significantly reduced tumor volume and increased survival
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