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Lysine-specific demethylase 4A (EC (EC (JmjC domain-containing histone demethylation protein 3A) (Jumonji domain-containing protein 2A) ([histone H3]-trimethyl-L-lysine(36) demethylase 4A) ([histone H3]-trimethyl-L-lysine(9) demethylase 4A) [JHDM3A] [JMJD2] [JMJD2A] [KIAA0677]


Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines.

Breast cancer is the one of the most frequent causes of female cancer mortality. KDM5A, a histone demethylase, can increase the proliferation, metastasis, and drug resistance of cancers, including breast cancer, and is thus an important therapeutic target. In the present work, we performed hierarchical virtual screening towards the KDM5A catalytic pocket from a chemical library containing 90,000 compounds. Using multiple biochemical methods, the cyclopenta[c]chromen derivative was identified as the top candidate for KDM5A demethylase inhibitory activity. Compared with the well-known KDM5 inhibitor CPI-455 ( ), exhibited higher potency against KDM5A and much higher selectivity for KDM5A over both KDM4A and other KDM5 family members (KDM5B and KDM5C). Additionally, compound repressed the proliferation of various KDM5A-overexpressing breast cancer cell lines. Mechanistically, promoted accumulation of p16 and p27 by blocking KDM5A-mediated H3K4me3 demethylation, leading to cell cycle arrest and senescence. To date, compound is the first cyclopenta[c]chromen-based KDM5A inhibitor reported, and may serve as a novel motif for developing more selective and efficacious pharmacological molecules targeting KDM5A. In addition, our research provides a possible anti-cancer mechanism of KDM5A inhibitors and highlights the feasibility and significance of KDM5A as a therapeutic target for KDM5A-overexpressing breast cancer.


  • Jumonji domain
  • KDM5A
  • breast cancer
  • cell cycle arrest
  • cell senescence
  • histone demethylation
  • protein-protein interaction
  • virtual screening