Oral Presentation Royal Australian Chemical Institute National Congress 2026

Design, synthesis and analysis of selective KDM4 inhibitors as chemical tool compounds (136917)

Jennifer R Baker 1 , Angus J Saxton 2 , Jayden Sterling 3 , Lenka Munoz 3
  1. School of Science, University of Wollongong, Wollongong, NSW, Australia
  2. School of Science, University of Newcastle, Callaghan, NSW, Australia
  3. School of Medical Sciences, University of Sydney, Sydney, NSW, Australia

The histone lysine demethylase family of enzymes KDM4 comprise six members, KDM4A-F. KDM4A-C demethylate histone lysine substrates H3K9me2/me3 and H3K36me2/me3, while KDM4D selectively demethylates H3K9me2/me3.1 KDM4E/F were previously considered pseudogenes, however some tissue expression has been reported.2 The KDM4 family of enzymes plays a critical role in regulating gene activity, acting as molecular switches that determine when key genes are turned on or off. In healthy cells, this fine control is essential for normal growth and repair.3 However, in many cancers—including breast, lung, colorectal, brain, and blood cancers—KDM4 enzymes are overproduced. This disrupts tumour-suppressing pathways, activates cancer-promoting genes, and drives aggressive behaviours such as uncontrolled growth and metastasis.1,3 Despite their clear involvement in cancer, there are currently no selective inhibitors available for KDM4A-D, leaving a significant gap in both research and therapeutic development.4,5 This project addresses that gap by developing the first selective inhibitors of KDM4 enzymes. To date, this work has produced >400 novel small molecules that inhibit KDM4A at levels as low as ​40 nM. A selection of these compounds offer significant selectivity to KDM4 over known inhibitor off-targets proteins. These molecules will serve as powerful research tools to better understand KDM4’s role in health and disease, and as a foundation for the design of new targeted cancer therapies. By enabling precise intervention in epigenetic regulation, this work has the potential to improve cancer treatment strategies, reduce off-target effects, and open new avenues for personalised medicine.6 Ultimately, it provides both immediate research benefits and long-term medical impact in the fight against cancer.

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