Targeting LSD1 and HDAC6/8: Advancing Dual Inhibitors for Cancer Therapy

The study explores the role of Lysine Specific Demethylase 1 (LSD1) in cancer and its potential as a therapeutic target. LSD1, an enzyme linked to various malignancies, can be targeted to reactivate genes that have been silenced abnormally. The research suggests that LSD1 may play a role in the development of acute myelogenous leukemia (AML) by hindering the differentiation-promoting function of ATRA. The paper also discusses the development of selective inhibitors for HDAC isoforms, which are being considered as less toxic options compared to broad HDAC inhibitors. Notably, the combination of LSD1 and HDAC inhibitors has shown increased effectiveness against cancer.

The research introduces JBI-295, a dual inhibitor that targets LSD1 and HDAC6/8, demonstrating enhanced efficacy without increased systemic toxicity in certain AML and JAK-dependent cancers. The methodology involved computational chemistry to design specific inhibitors, with TR-FRET and fluorescence-based assays to measure LSD1 and HDAC activity, respectively. Western blotting was utilized to evaluate the inhibition of LSD1 and HDAC, and Alamar blue cytotoxicity assay was employed to assess cell growth.

The results indicate that several compounds were potent against LSD1 and highly selective against MAOs. JBI-295, as a leading dual molecule, displayed potent LSD1 inhibition and selective HDAC6/8 activity, with significant selectivity over other HDAC isoforms. It also showed strong anti-proliferative effects on leukemia and multiple myeloma cell lines. Both in vitro and in vivo studies revealed increased levels of CD11b, CD86, GFI1b, and tubulin acetylation upon treatment with JBI-295. The compound was more effective in inhibiting leukemia growth in a xenograft model compared to a selective HDAC6 inhibitor and showed enhanced tumor growth inhibition in a melanoma model. Furthermore, JBI-295 demonstrated single-agent activity in a murine colon cancer model and enhanced tumor growth inhibition when combined with an anti-PDL1 antibody.

The study concludes that dual LSD1-HDAC6/8 inhibitors, such as JBI-295, could be promising new therapeutic agents for a specific subset of cancers. Ongoing studies are focused on further evaluating the efficacy and toxicology of JBI-295.