Reversible inhibition of lysine-specific demethylase 1 is a novel therapeutic strategy for solid tumors

Cancer is a genomic disease driven by interplay between genetic and epigenetic factors. While genetic mutations are irreversible events, epigenetic regulation is dynamic and reversible, and small molecule blockade of the epigenetic machinery has shown clinical benefit in hematological malignancies. However, the promise of epigenetic therapy has yet to be realized in solid tumors due do limited efficacy and elevated risk of toxicity. Development of potent and specific inhibitors targeting the histone methylation machinery shows promise in tailoring epigenetic therapy for a specific malignancy and decreasing the risk of off-target effects. One such target of interest is the histone lysine-specific demethylase 1 (LSD1). Several solid malignancies show upregulation of LSD1 associated with an aggressive clinical course. Validation of LSD1 as a target has been limited by poorly potent and nonspecific tool compounds, hindering evaluation in in vivo models of disease. This work describes the discovery of a novel potent, specific, and reversible series of LSD1 inhibitors. The identified lead compound, HCI2509, is a noncompetitive inhibitor with nanomolar affinity for LSD1. HCI2509 impaired cell viability across several human cancer cell lines, with both Ewing sarcoma and endometrial cancers showing particularly potent responses. Ewing sarcoma is a rare and aggressive pediatric malignancy characterized by by the chromosomal translocation-derived EWS/ETS fusion proteins. EWS/ETS fusions act iv as oncogenic transcription factors and facilitate cellular reprogramming through the activation of oncogenes and repression of tumor suppressors. Treatment with HCI2509 reverses both EWS/ETS-mediated transcriptional activation and transcriptional repression, and leads to apoptotic cell death in Ewing sarcoma cells. Notably, HCI2509 shows single-agent efficacy in xenograft models of Ewing sarcoma and represents a new therapeutic strategy for this devastating disease. HCI2509 also shows single-agent efficacy in a xenograft model of Type II endometrial carcinoma. Cases of Type II endometrial carcinoma comprise 11% of the incidence and 48% of the deaths due to endometrial cancer annually, such that new therapies are needed for this aggressive subtype. Reversible LSD1 inhibition was associated with tumor regression in an orthotopic model of this disease. These results demonstrate the promise of targeting the histone methylation machinery, specifically LSD1, as a therapeutic strategy for solid tumors.