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Nitroreductase-Mediated Release of Inhibitors of Lysine-Specific Demethylase 1 (LSD1) from Prodrugs in Transfected Acute Myeloid Leukaemia Cells

preprint
submitted on 22.10.2019 and posted on 24.10.2019 by Manfred Jung, Eva-Maria Herrlinger, Mirjam Hau, Desiree M. Redhaber, Gabriele Greve, Dominica Willmann, Simon Steimle, Michael Müller, Michael Lübbert, Cornelius Miething, Roland Schüle
Lysine-specific demethylase 1 (LSD1) has evolved as a promising therapeutic target for cancer treatment, especially in acute myeloid leukaemia (AML). To approach the challenge of site-specific LSD1 inhibition, we developed an enzyme-prodrug system with the bacterial nitroreductase NfsB (NTR) that was expressed in the virally transfected AML cell line THP1-NTR+. The cellular activity of the NTR was proven with a new luminescent NTR probe. We synthesised a diverse set of nitroaromatic prodrugs that by design do not affect LSD1 and are reduced by the NTR to release an active LSD1 inhibitor. The 2-nitroimidazolyl prodrug (1f) of a potent LSD1 inhibitor emerged as one of the best prodrug candidates with a pronounced selectivity window between wild-type and transfected NTR+ cells. Our prodrugs are selectively activated and release the LSD1 inhibitor locally in turn blocking colony formation. This system may be applied in future targeting approaches to reach tissue- or organ-type-specific inhibition of LSD1.

Funding

EXC 2189:  CIBSS - Centre for Integrative Biological Signalling Studies

Deutsche Forschungsgemeinschaft

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DFG CRC992

DFG CRC850

DFG CRC746

DFG Schu688/12-1

ERC AdGrant 32844

History

Email Address of Submitting Author

manfred.jung@pharmazie.uni-freiburg.de

Institution

University of Freiburg

Country

Germany

ORCID For Submitting Author

0000-0002-6361-7716

Declaration of Conflict of Interest

No conflict of interest

Version Notes

1.0 Original version 1.1. Abstract and keywords modified

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