A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric di-methylation of arginine residues, has been implicated in cancer stem cell homeostasis and shown to be a potential therapeutic target in MLL-fusion AMLs. However, given the toxicity of complete PRMT5 inhibition, there is a need to identify effective synergistic therapies. Through a targeted screen of compounds that inhibit key nodes of pathways either regulated by PRMT5 or known to be relevant for AML (e.g. intracellular signaling, splicing and transcription), we have identified a synthetic lethality between inhibition of LSD1, a lysine demethylase known to affect AML blast differentiation, and PRMT5. The two inhibitors broadly reshape the transcriptome of targeted cells and synergize to promote AML differentiation and eventually growth inhibition and apoptosis, in a p53-dependent manner. To leverage this synthetic lethal interaction, we have generated a new set of dual compounds that inhibit both PRMT5 and LSD1. Mechanistically, we show that these dual compounds elicit transcriptional and post-transcriptional (splicing) defects that recapitulate the combination therapy. Last, we were able to solve the X-ray co-crystal structure of one of the designed inhibitors with LSD1, thus elucidating its binding mode and providing a structural basis for the rational design of further inhibitors. In summary, our findings identify a novel drug combination strategy for the treatment of AML.