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A patent review of KDM4 histone demethylase inhibitors (2014-present)
Xiaolong Yang1,2, Yuyan Han1,2, Lei Yu3
1Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Introduction:
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.
Areas Covered:
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.
Expert Opinion:
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.
Insights
KDM4 inhibitors show promise for cancer treatment, but face challenges like poor cell penetration. Novel strategies and further research into KDM4 functions are crucial for developing effective therapeutics.
Area of Science:
- Oncology
- Biochemistry
- Medicinal Chemistry
Background:
- The KDM4 family of histone demethylases (KDM4A-F) are implicated in various cancers.
- Aberrant KDM4 expression presents therapeutic targets in oncology.
- TACH101 is an example of a KDM4 inhibitor in clinical trials.
Purpose of the Study:
- To review patent literature on KDM4 inhibitors.
- To analyze 17 patent applications from June 2014 to May 2025.
Main Methods:
- Systematic literature search using Cortellis Drug Discovery Intelligence.
- Critical analysis of identified patent applications.
Main Results:
- Significant progress in KDM4 inhibitor development.
- Current inhibitors face challenges: poor membrane permeability, limited cellular potency, and low isoform specificity.
Conclusions:
- Novel scaffolds, covalent inhibitors, protein degraders, and targeting non-catalytic domains are potential solutions.
- Further research on KDM4 biological roles is essential for rational drug design and clinical translation.
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