2. Academic Validation
  3. A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

A synergistic interaction between PRMT5 and LSD1 inhibitors in AML

  • Sci Adv. 2026 Mar 27;12(13):eaea4059. doi: 10.1126/sciadv.aea4059.
Nesteene Joy Param 1,  Elisa Arceci 1,  Francesco Fiorentino 2 3,  Luca Pignata 4 5,  Denis Torre 1,  Nayeli Gutiérrez-Trejo 1,  Jia Yi Fong 4 5,  Pierre-Alexis Goy 4 5,  Brenda Y Han 4 5,  Chiara Lambona 2,  Elisabetta Di Bello 2,  Carola Castiello 2,  Marco Barone 6,  Megan Schwarz 1,  Cheryl Arrowsmith 7,  Koichi Ito 8,  Peggy Scherle 8,  Dave Keng Boon Wee 4,  Steven Ndoye 1,  Tommaso Tabaglio 4 5,  Anand D Jeyasekharan 9 10,  Manikandan Lakshmanan 4,  Roberto Cirilli 11,  Hansjörg Habisch 12 13,  Tobias Madl 12 13,  Andrea Mattevi 6,  Sergio Valente 2,  Antonello Mai 2,  Ernesto Guccione 1
Affiliations

Affiliations

  • 1 Center for OncoGenomics and Innovative Therapeutics (COGIT); Center for Therapeutics Discovery, Department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY, New York, USA.
  • 2 Department of Drug Chemistry and Technologies, Sapienza University of Rome, 00185 Rome, Italy.
  • 3 Department of Biochemical Sciences, Sapienza University of Rome, 00185 Rome, Italy.
  • 4 Institute of Molecular and Cell Biology, Agency for Science, Technology and Research (A*STAR), Singapore 138673, Singapore.
  • 5 Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119077, Singapore.
  • 6 Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy.
  • 7 SGC Toronto, Toronto, Canada.
  • 8 Prelude Therapeutics, Wilmington, DE, USA.
  • 9 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 10 Department of Haematology-Oncology, National University Hospital, Singapore, Singapore.
  • 11 Centre for the Control and Evaluation of Medicines, Chemical Medicines Unit, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
  • 12 Gottfried Schatz Research Center for Cell Signaling, Metabolism and Aging, Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
  • 13 BioTechMed-Graz, Graz, Austria.
PMID: 41894488 DOI: 10.1126/sciadv.aea4059
Abstract

Acute myeloid leukemia (AML) is a hematopoietic malignancy caused by abnormal proliferation and differentiation of blasts. PRMT5, a methyltransferase that catalyzes symmetric dimethylation of arginine (SDMA) residues, has been implicated in Cancer stem cell homeostasis and shown to be a potential therapeutic target in AML. 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 PRMT5-regulated pathways, we identified a synthetic lethality between inhibition of PRMT5 and LSD1, a lysine demethylase known to affect AML blast differentiation. 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 generated new dual compounds to inhibit both Enzymes and recapitulated the effects of the drug combination. Our results uncover an unexpected convergence of PRMT5- and LSD1-regulated targets, paving the way for new therapeutic opportunities.

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