Identification of novel inhibitors of histone acetyltransferase hMOF through high throughput screening

• Published in: European journal of medicinal chemistry Vol. 157; pp. 867 - 876
• Main Authors: Zhang, Rukang, Wang, Jiang, Zhao, Liang, Liu, Shien, Du, Daohai, Ding, Hong, Chen, Shijie, Yue, Liyan, Liu, Yu-Chih, Zhang, Chenhua, Liu, Hong, Luo, Cheng
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 05-09-2018
• Subjects: Epigenetics; High throughput screening; Histone acetyltransferase; Inhibitor; MOF; High throughput screening; Epigenetics; Inhibitor; MOF; Histone acetyltransferase
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.08.026

The histone acetyltransferases (HATs) in mammals include GCN5 N-acetyltransferases, the MOZ, YBF2, SAS2, and TIP60 proteins, and the orphan HATs. The males absent on the first (MOF) is mainly related to acetylation of histone H4 Lys16 and has influence on downstream genes expression. However, the only inhibitor MG149 presented low activity against MOF. Besides, there was no high throughput screening platform on MOF, which limited the inhibitor discovery and functional study. In our study, we set up a high throughput screening platform based on amplified luminescent proximity homogeneous assay (ALPHA), which led us to a moderate inhibitor DC_M01. By chemical modification, we found DC_M01_7, which was the analog of DC_M01 with an IC50 value of 6 μM. DC_M01_7 significantly inhibited HCT116 cells proliferation and could also inhibit histone 4 lysine 16 acetylation in HCT116 cells. To sum up, our work will probably assist the further development of more potent MOF inhibitors and the functional study of hMOF.
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•We identified a potent hMOF inhibitor with a new scaffold using high throughput screening.•The binding affinity of the hit compound DC_M01 was measured by SPR.•DC_M01_7, which was obtained by chemical modification, could inhibit hMOF activity in a substrate competitive mode.•DC_M01_7 could inhibit hMOF activity in HCT116 cells and regulate downstream genes.