Advancements in Cancer Therapy: Targeting LSD1 and HDAC6/8 with Dual Inhibitors

LSD1, a component of the CoREST complex, plays a role in cancer cell proliferation and survival by interacting with HDAC within the complex. The combined targeting of LSD1 and HDAC has been found to be more effective in combating glioblastoma, AML, and breast cancer, suggesting that dual inhibitors could offer a strategic advantage in cancer treatment without increasing systemic toxicity from multiple drugs.

A series of molecules with either LSD1 or dual LSD1-HDAC activity were developed using computational chemistry. The in vitro potency of these compounds against LSD1 was evaluated using a TR-FRET assay, and their HDAC activity was measured with a fluorimetric assay. Biomarkers for LSD1 and HDAC inhibition were assessed through Western blotting and RT qPCR, while cell proliferation was gauged by an Alamar blue cytotoxicity assay.

One of the compounds, JBI-097, showed exceptional selectivity and potency as a dual inhibitor, with an IC50 of 0.007μM for LSD1 and IC50 values of 0.06μM and 0.1μM for HDAC6 and HDAC8, respectively. JBI-097 demonstrated robust antiproliferative effects on leukemia and multiple myeloma cell lines, outperforming both LSD1 and HDAC6 inhibitors when used individually. In vivo and cell-based target engagement studies indicated an increase in biomarkers such as CD11b, CD86, GFI1b, and tubulin acetylation levels.

JBI-097 was more effective in inhibiting tumor growth in a HEL92.1.7 xenograft model when administered orally compared to the intraperitoneal administration of an HDAC inhibitor. Furthermore, in a MM.1S tumor model, JBI-097 showed a stronger inhibitory effect on tumor growth than single-agent treatments with LSD1 or HDAC6 inhibitors. The combination of JBI-097 with topotecan led to the complete inhibition of tumor growth in the MM.1S xenograft model.

The findings indicate that it is viable to design dual LSD1-HDAC6/8 inhibitors that maintain individual activity and significantly suppress cell proliferation, presenting these inhibitors as potential powerful therapeutic agents for cancer treatment. Ongoing research is focused on understanding the underlying mechanisms to identify the most effective compounds.

The research was presented by Sivanandhan Dhanalakshmi, Sridharan Rajagopal, and colleagues at the American Association for Cancer Research Annual Meeting in 2018.