A patent review of KDM4 histone demethylase inhibitors (2014-present)

The KDM4 family of histone demethylases, characterized by a conserved JmjC catalytic domain, comprises six subtypes: KDM4A – F. Aberrant expression of these enzymes has been associated with tumorigenesis across various malignancies, highlighting their potential as therapeutic targets in oncology. To date, a series of KDM4 inhibitors have been developed, among which TACH101 is undergoing clinical evaluation for cancer treatment.
This review provides a comprehensive overview of the patent literature on KDM4 inhibitors, derived from a systematic search utilizing the Cortellis Drug Discovery Intelligence database. A total of 17 patent applications, published within the period from June 2014 to May 2025, were identified and critically analyzed.
Significant progress has been achieved in the development of KDM4 inhibitors; however, most current compounds continue to face major challenges, including poor membrane permeability, limited cellular potency, and low isoform specificity. Strategies such as designing inhibitors with novel scaffolds, developing covalent inhibitors, advancing protein degraders, and targeting non-catalytic domains may provide viable solutions to these limitations. In addition, the physiological and pathological roles of KDM4 remain insufficiently characterized. Further in-depth investigations into the biological functions of KDM4 will be essential to guide the rational design and facilitate the clinical translation of KDM4-targeted therapeutics.