Novel potent inhibitors of the histone demethylase KDM1A (LSD1), orally active in a murine promyelocitic leukemia model

Paolo Trifirò, Anna Cappa, Silvia Brambillasca, Oronza A. Botrugno, Maria Rosaria Cera, Roberto Dal Zuffo, Paola Dessanti, Giuseppe Meroni, Florian Thaler, Manuela Villa, Saverio Minucci, Ciro Mercurio, Mario Varasi, Paola Vianello

Research output: Contribution to journalArticlepeer-review


Background: Histone lysine demethylases (KDMs) are well-recognized targets in oncology drug discovery. They function at the post-translation level controlling chromatin conformation and gene transcription. KDM1A is a flavin adenine dinucleotide-dependent amine oxidase, overexpressed in several tumor types, including acute myeloid leukemia, neuroblastoma and non-small-cell lung cancer. Among the many known monoamine oxidase inhibitors screened for KDM1A inhibition, tranylcypromine emerged as a moderately active hit, which irreversibly binds to the flavin adenine dinucleotide cofactor. Material & methods: The KDM1A inhibitors 5a-w were synthesized and tested in vitro and in vivo. The biochemical potency was determined, modulation of target in cells was demonstrated on KDM1A-dependent genes and the anti-clonogenic activity was performed in murine acute promyelocytic Leukemia (APL) blasts. An in vivo efficacy experiment was conducted using an established murine promyelocytic leukemia model. Results: We report a new series of tranylcypromine derivatives substituted on the cyclopropyl moiety, endowed with high potency in both biochemical and cellular assays. Conclusion: The most interesting derivative (5a) significantly improved survival rate after oral administration in a murine model of promyelocitic leukemia.

Original languageEnglish
Pages (from-to)1161-1174
Number of pages14
JournalFuture Medicinal Chemistry
Issue number11
Publication statusPublished - Jul 1 2017


  • cancer therapy
  • epigenetic
  • KDM1A
  • LSD1
  • lysine demethylase
  • promyelocytic leukemia
  • tranylcypromine

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Drug Discovery


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