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

Future Med Chem 2017 07 19;9(11):1161-1174. Epub 2017 Jul 19.

Department of Experimental Oncology, Academic Drug Discovery, European Institute of Oncology, Ifom-IEO-Campus, via Adamello 16, 20139 Milan, Italy.

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.

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http://dx.doi.org/10.4155/fmc-2017-0003DOI Listing
July 2017
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