Therapeutic targeting of p300/CBP HAT domain for the treatment of NUT midline carcinoma

摘要

Chemical probe screening in three tumor cell lines. HCC2429, NUT midline carcinoma; Patu8988T, pancreatic ductal adenocarcinoma; QGP-1, pancreatic neuroendocrine tumor. Cells were incubated with each of the chemical probes at a concentration of 10 µM for 72 h and cell viabilities were measured by CellTiter Glo Cell Viability assay. The values were normalized to dimethyl sulfoxide (DMSO)-treated samples and a heatmap was generated based on the mean values of three independent experiments. The heat map was colored according to normalized cell viability as depicted in the figure capture. The -values of positive hits (JQ1, A-485 and BTOZ-1) were presented in the text. Venn diagram analysis showing NMC-selective and -unselective inhibitors. Probes with cell viability less than 50% in at least one cell line from the screening above were chosen as potent hits. IC of A-485 on three NMC cell lines and six cell lines of other tumor identities. Mean ± SEM from three independent experiments, *  ≤ 0.05. Comparison of the growth effects A-485 (red circles) and the inactive analogue A-486 (black square) on three NMC cell lines. IC of A-485 is shown in the graph. Mean ± SD from three technical replicates. In ( ) and ( ), cells were incubated with inhibitors at a concentration range between 10 nM and 25 µM. Cell viability was monitored after 72 h by CellTiter Glo Cell Viability assay. The dose response curve was used to determine the IC50 by Prism.