YK1 is a potent and selective PPI inhibitor for ELF3-MED23 with IC50 of 1.18 uM, 95 % inhibition at 10 uM, attenuates the HER2-mediated oncogenic signaling cascades.
YK1 has IC50 of 0.91 uM and Ki of 0.78 uM in fluorescence polarization assays.
YK1 directly bind to MED23 via forming H-bonds with D400 and H449 residues.
YK1 specifically bound to MED23 391-462 region and interfered with the ELF3-MED23 PPI.
YK1 is specific to ELF3-MED23, does not disturb PPIs between MED23 and its known partner transcription factors, such as ELK1 and IRF7.
YK1 also not exhibit significant inhibitory activity against any of HER family kinases (EGFR, ErbB2, and ErbB4) or AKT/MAPK pathway-related kinases (PI3 kinase and c-RAF).
YK1 more potently inhibits the cell growth of NCI-N87, which highly expresses HER2 (IC50 = 1.56 μM), but almost non-cytotoxic in normal mammalian cells, indicating that the antiproliferative activity of YK1 is dependent on HER2 overexpression.
YK1 (4 mg/kg, i.v.) facilitated significant tumor growth retardation with significant reduction in tumor volume of NCI-N87 xenograft mice, also promoted apoptosis markedly in a dose-dependent manner.