Unmet Need: Epigenetic regulation of gene expression is one mechanism that can be dysregulated in the development of diseases such as cancer and has specifically been implicated in the the development of therapeutic resistance mechanisms in cancer and tumor metastasis. There remains a significant need for the development of novel epigenetic therapeutic strategies that target these pathways in a potent and specific fashion.
Technical Details: Johns Hopkins researchers have developed a novel hybrid compound that potently and specifically inhibits the epigenetic regulatory complex CoREST for the treatment of disease. LSD1 and HDAC1/2 comprise the main enzymatic functions of the epigenetic CoREST complex, and LSD1 has been shown to be upregulated in a number of cancers. Prior work has shown that inhibition of LDS1 and/or HDAC1/2 in a disease state leads to reversal of aberrant gene silencing. Administration of a potential lead compound “Corin” to a large panel of human melanoma cell lines resulted in more potent and sustained anti-proliferative effects than LSD1 or HDAC inhibitors alone or in combination. In addition, transcriptomic analysis showed Corin to be a more powerful inducer of tumor suppressor genes than individual LSD1 or HDAC inhibitors alone, or in combination. Corin has also been shown to target colorectal cancers, breast cancers, and diffuse pontine glioma brain tumors. Moreover, Corin has demonstrated anticancer effects through enhanced cancer immune surveillance. Overall, this novel hybrid compound represents a unique epigenetic targeting molecule to more potently and specifically target the CoREST regulatory complex than available mono-target molecules in the treatment of disease and serves as a proof-of-concept strategy for the development of additional dual-acting potent and specific epigenetic therapeutics.
Value Proposition:
· Hybrid compound targets both LSD1 and HDAC1/2 to increase inhibitory effects
· Novel epigenetic therapeutic with broader therapeutic window than existing drugs
· Increased specificity and therefore less toxic than individual LSD1/HDAC inhibitors
· Sensitizer to enhances efficacy of immunotherapeutics and overcomes epigenetic resistance of targeted therapies
· Broad application to many cancer types including demonstrated proof-of-concept mouse models in melanoma, and possible role for treating neurodegenerative diseases
Looking for Partners to: Develop & commercialize the technology as a novel epigenetic therapeutic strategy to sensitize and enhance responsiveness to immunotherapeutics and targeted drugs for cancers including melanoma.
Stage of Development: Pre-Clinical
Publication(s): Kalin, JH et al. (2018). Targeting the CoREST complex with dual histone deacetylase and demethylse inhibitors. Nat Comm 9:53. Anastas, JN et al. (2019) Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG. Cancer Cell 36(5):528-544. Xiong, Y et al. (2020) Inhibiting the coregulator CoREST impairs Foxp3+ Treg function and promotes antitumor immunity. J Clin Invest 130(4):1830-1842. Miller SA, Policastro RA, et al. (2020) Lysine-specific Demethylase 1 mediates AKT activity and promotes Epithelial-to-Mesenchymal transition in PIK3CA-mutant colorectal cancer. Mol Cancer Res 18(2):264-277.
