Design and synthesis of quinazoline derivatives as novel JMJD3/HDAC dual-target inhibitors

Epigenetic drugs offered a novel disease therapeutic strategy by reversibly modulating gene expression. For instance, inhibitors targeting histone lysine demethylases (KDMs) and histone deacetylases (HDACs) demonstrated significant potential in combating complex diseases such as cancer and neurological diseases. However, single-target inhibitors often exhibit limited efficacy or resistance due to the complexity of disease mechanisms and the activation of compensatory pathways. To address these limitations, a series of novel quinazoline derivatives were designed and synthesized as potent dual inhibitors targeting histone lysine demethylase JMJD3 and histone deacetylases. Through systematic structural optimization, lead compound 6a was identified with nanomolar potency: JMJD3 (IC₅₀ = 545 nM), HDAC1/2/3/6/10 (IC₅₀ = 1.1/3.5/4.4/16/8.3 nM), along with significant selectivity over related isoforms including JMJD1B, JMJD2A and HDAC8. The cellular enzymatic inhibition activity was validated in triple-negative breast cancer (TNBC) cell lines MDA-MB-231 and HCC1806, where 6a dose-dependently elevated the levels of H3K27 methylation (me1/me2/me3) and H3 acetylation. The therapeutic potential of these JMJD3/HDAC inhibitors was further evaluated in TNBC cell models, where they exhibited potent antiproliferative activity and induced cell cycle arrest. Compared with previously reported JMJD3/HDAC dual inhibitors, 6a demonstrates superior nanomolar potency against both targets. As a highly potent lead, 6a provides a novel scaffold for dual-target epigenetic drug discovery, a valuable chemical probe for investigating epigenetic crosstalk, and a promising candidate for cancer therapy.