In 2004, lysine-specific demethylase 1 (LSD1) was first identified as a histone demethylase by the Shi lab at Ludwig Cancer Research Oxford, overturning the long-standing belief that histone methylation was irreversible. This landmark discovery opened new avenues for understanding epigenetic regulation and its role in cancer.
Since then, LSD1 has emerged as a critical oncogenic player, particularly in haematological malignancies such as acute myeloid leukaemia. Significant efforts have been devoted to developing small-molecule inhibitors targeting the enzymatic activity of LSD1, many of which have entered clinical trials.
However, growing evidence reveals that LSD1 also exerts essential noncatalytic, scaffolding functions, particularly relevant in acute myeloid leukaemia pathogenesis, that aren’t addressed by traditional enzymatic inhibitors. To overcome this limitation, Amir Hosseini and colleagues from the Shi lab have now developed and characterised the first selective PROTAC-based LSD1 degrader, which effectively eliminates LSD1 protein, thereby targeting both its catalytic and scaffolding roles. Notably, it promotes acute myeloid leukaemia cell differentiation and sensitises non-acute promyelocytic leukaemia AML cells to all-trans retinoic acid.
Taken together, this study positions the degrader as a powerful chemical tool to study LSD1 biology and a promising therapeutic candidate for acute myeloid leukaemia.
Read the full article in PNAS online: https://www.pnas.org/doi/10.1073/pnas.2425812122