Discovery of a novel BRD4 inhibitor for the treatment of acute myeloid leukemia.

Abstract

Bromodomain-containing protein 4 (BRD4), an epigenetic regulatory reader, is closely related to the development of various cancers, so it has emerged as one of the most extensively investigated therapeutic targets for tumors. However, no BRD4 inhibitors have received clinical approval to date, underscoring the significance of developing novel BRD4 inhibitors. Herein, we reported a series of triazolopyridine-based compounds demonstrating promising inhibitory activities against BRD4. Among these, compound 15 (SLJY-36) was identified as lead compound, exhibiting significant binding affinity for BRD4 BD1, with IC50 value of 14.81 nM and a selectivity of 14-fold for BD1 over BD2. SLJY-36 exhibited an IC50 value of 1.03 μM against MV4-11 cell line and effectively induced apoptosis in acute myeloid leukemia (AML) cells in vitro and inhibited tumor growth in vivo. Additionally, SLJY-36 broadly regulated gene expression in MV4-11 cells. It exerted inhibitory effects on AML progression by downregulating pathways such as SCHLOSSER MYC TARGETS REPRESSED BY SERUM. These findings indicate the potential of SLJY-36 as a novel lead compound for the treatment of AML.