Lysine demethylase (KDM) inhibitors for the treatment of cancer: a patent review (2015-present)

Introduction: Lysine demethylases (KDMs) are crucial epigenetic regulators that modulate gene expression via demethylation of histone and non-histone proteins, playing a pivotal role in cancer progression. Dysregulation of KDM activity, particularly in KDM1A, KDM4, KDM5, and KDM6, has been linked to several cancers, including leukemia and breast, lung, and prostate cancers, leading to the emergence of KDM inhibitors (KDMi) as promising therapeutic agents. These inhibitors target KDMs by mimicking cofactors, chelating metal ions, or competing with histone substrates to disrupt demethylation. Some of the most studied KDMi are those targeting KDM1A. Areas covered: In this review, we critically explore the complex roles of KDMs in cancer, provide a detailed overview of patents describing KDMi published from 2015 to the present, and assess European clinical trials investigating KDMi developed for cancer therapy. Expert opinion: Despite the promising potential of KDMi, their clinical development is hampered by significant challenges including safety concerns, suboptimal patient enrollment, and difficulties in optimizing dosing regimens and identifying reliable biomarkers. Future research must focus on refining dosing protocols, discovering predictive biomarkers, and developing effective combination therapies to maximize patient outcomes, ultimately realizing the full promise of KDMi in cancer treatment.