HCI-2509: Targeting LSD1 to Combat ER-Negative Breast Cancer

The abstract discusses the role of lysine-specific demethylase 1 (LSD1) in regulating gene expression through histone demethylation, which can either activate or repress transcription depending on the lysine residue involved. LSD1's demethylation of the transcription-activating mark H3K4me2 is implicated in the suppression of tumor suppressor genes, while its activity on the repressive mark H3K9 promotes tumor growth. Elevated LSD1 levels are found in ER-negative breast cancers, where its overexpression is linked to aggressive cancer behavior. The development of LSD1 inhibitors as antitumor agents is highlighted, with a focus on the need for more potent and specific inhibitors that do not possess monoamine oxidase activity.

The authors describe a structure-based drug discovery approach that led to the identification of a lead compound, HCI-2509, which showed potent inhibition of LSD1 with an IC50 of 13 nM and demonstrated specificity by showing minimal inhibition against five related enzymes. HCI-2509 treatment in cell lines resulted in increased H3K4 methylation levels. The compound was tested for its effect on cell viability across a range of cancer cell lines, particularly showing sensitivity in ER-negative breast cancer cell lines. The activity of HCI-2509 was also confirmed in cells derived from ER-negative breast cancer patients. Furthermore, the authors developed a gene expression signature linked to sensitivity to HCI-2509 by analyzing the response of breast cancer cell lines to the compound. The ongoing work aims to explore the therapeutic potential of HCI-2509 in treating ER-negative breast cancers using mouse models.

The citation for this abstract is from the Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research, held in Chicago from March 31 to April 4, 2012, published in Cancer Research 2012;72(8 Suppl), with the abstract number 1045.