Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer

Area of Science:

• Oncology
• Epigenetics
• Pharmacology

Background:

• Epigenetic regulators like lysine-specific demethylase 1 (LSD1) and histone deacetylases (HDACs) are crucial in cancer cell proliferation.
• Dual targeting of LSD1 and HDACs, particularly HDAC6, offers a potential strategy to inhibit tumor growth by modulating gene expression.

Purpose of the Study:

• To evaluate the in vitro and in vivo efficacy of JBI-097, a novel dual inhibitor of LSD1 and HDAC6, across various cancer models.
• To assess the anti-proliferative effects and biomarker modulation of JBI-097 in cancer cell lines and tumor models.

Main Methods:

• Enzymatic assays to determine the inhibitory potency and isoform selectivity of JBI-097 against LSD1 and HDAC6.
• Cell-based proliferation assays using hematological and solid tumor cell lines.
• In vivo studies in xenograft and syngeneic mouse models of various cancers, including combination therapies.

Main Results:

• JBI-097 exhibited potent inhibition of LSD1 and HDAC6 enzymatic activities with selectivity over other HDAC isoforms.
• Significant anti-proliferative effects were observed in both hematological and solid tumor cell lines.
• JBI-097 demonstrated robust in vivo efficacy in multiple myeloma, erythroleukemia, and CT-26 tumor models, both as monotherapy and in combination regimens.

Conclusions:

• JBI-097 is a promising dual LSD1/HDAC6 inhibitor with significant preclinical anti-cancer activity.
• The findings support further investigation of JBI-097 as a therapeutic agent for various cancers, including combination strategies with standard treatments or immune checkpoint inhibitors.