Exploring the potential of histone demethylase inhibition in multi-therapeutic approaches for cancer treatment.

Histone demethylases play a critical role in gene transcription regulation and have been implicated in cancer. Numerous reports have highlighted the overexpression of histone demethylases, such as LSD1 and JmjC, in various malignant tumor tissues, identifying them as effective therapeutic targets for cancer treatment. Despite many histone demethylase inhibitors entering clinical trials, their clinical efficacy has been limited. Therefore, combination therapies based on histone demethylase inhibitors, along with other modulators like dual-acting inhibitors, have gained significant attention and made notable progress in recent years. In this review, we provide an overview of recent advances in drug discovery targeting histone demethylases, focusing specifically on drug combination therapy and histone demethylases-targeting dual inhibitors. We discuss the rational design, pharmacodynamics, pharmacokinetics, and clinical status of these approaches. Additionally, we summarize the co-crystal structures of LSD1 inhibitors and their target proteins as well as describe the corresponding binding interactions. Finally, we also provided the challenges and future directions for utilizing histone demethylases in cancer therapy, such as PROTACs and molecular glue etc.