Discovery of selenium-containing amino acid derivatives as novel ENL YEATS domain inhibitors via AlphaScreen-based high throughput screening.

Eleven-Nineteen-Leukemia Protein (ENL), a member of YEATS domain family, is a novel reader of lysine acetylation. Its deregulation is linked to various human diseases, especially cancer. Therefore, ENL has garnered significant interest as a potential therapeutic target. Herein, we report the discovery of novel ENL YEATS domain inhibitors via high-throughput screening. Hit compounds DC_E35 and DC_E36 were identified and structurally optimized, yielding the potent derivative DC_E35_5d (IC50 = 62.0 ± 14.7 nM). Biophysical assays confirmed direct target engagement. In MOLM-13 cells, DC_E35_5d reduced ENL thermal stability, downregulated the oncogene MYC, and synergized with the Bromodomain inhibitor JQ-1 to suppress cell growth. Hence, DC_E35_5d represents a novel class of ENL YEATS domain inhibitors with novel scaffold and has broad prospects for being a probe for ENL-related academic and clinical research.