Discovery of an efficacious KDM5B PROTAC degrader GT-653 up-regulating IFN response genes in prostate cancer
- Eur J Med Chem. 2024 Jun 5:272:116494. doi: 10.1016/j.ejmech.2024.116494.
- 1. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
- 2. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China. Electronic address: [email protected].
- 3. Shanghai Key Laboratory of Regulatory Biology, The Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, 200241, China; School of Pharmaceutical Sciences and Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Kunming, Yunnan, 650500, China. Electronic address: [email protected].
Epigenetic alterations promote Cancer development by regulating the expression of various oncogenes and anti-oncogenes. Histone methylation modification represents a pivotal area in epigenetic research and numerous publications have demonstrated that aberrant histone methylation is highly correlated with tumorigenesis and development. As a key Histone Demethylase, lysine-specific demethylase 5B (KDM5B) demethylates lysine 4 of histone 3 (H3K4) and serves as a transcriptional repressor of certain tumor suppressor genes. Meanwhile, KDM5B inhibits STING-induced intrinsic immune response of tumor cells or recruits SETDB1 through non-enzymatic function to silence reverse transcription elements to promote immune escape. The conventional small molecule inhibitors can only inhibit the enzymatic function of KDM5B with no effect on the non-enzymatic function. In the article, we present the development of the first series of KDM5B degraders based on CPI-455 to inhibit the non-enzymatic function. Among them, GT-653 showed optimal KDM5B degradation efficiency in a ubiquitin proteasome-dependent manner. GT-653 efficiently reduced KDM5B protein levels without affecting KDM5B transcription. Interestingly, GT-653 increased H3K4me3 levels and activated the type-I interferon signaling pathway in 22RV1 cells without significant phenotypic response on cell proliferation.