Exploring the Therapeutic Potential of JBI-802: A Dual Inhibitor Targeting LSD1 and HDAC6 in Cancer Treatment

The abstract discusses the role of Lysine Specific Demethylase 1 (LSD1) in various cancers and the potential of inhibiting LSD1 for cancer treatment. It highlights the effectiveness of LSD1 down-regulation in inducing the re-expression of genes that are abnormally silenced, which can lead to the treatment of cancers. The study focuses on the development of a dual inhibitor, JBI-802, which targets both LSD1 and HDAC6/8, and has shown promising results in treating several types of cancer, including acute myelogenous leukaemia (AML), lymphoma, and others.

The methodology involved computational chemistry to design specific inhibitors, followed by in vitro assays to assess LSD1 and HDAC activity. Biomarkers and cell proliferation were evaluated using Western blotting, quantitative PCR, and Alamar blue cytotoxicity assay. In vivo efficacy was tested using xenograft and syngeneic models.

Results indicated that JBI-802 displayed strong potency against LSD1 with high selectivity, and it was particularly effective against AML, CLL, SCLC, sarcoma, and multiple myeloma cell lines. The compound showed significant target engagement and inhibited tumor growth more effectively than single inhibitors. It also demonstrated comparable activity to anti-PD-1/PD-L1 antibodies in a colon cancer model and enhanced tumor growth inhibition when combined with these antibodies. The compound was found to be well-tolerated up to a certain dosage.

The conclusion suggests that dual LSD1-HDAC6/8 inhibitors like JBI-802 could be new and effective therapeutic agents for treating a specific subset of AML and other cancers. The study is progressing towards IND-enabling studies to develop this inhibitor as a clinical candidate. The research was presented at the Annual Meeting of the American Association for Cancer Research in 2020.