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Bioorg Med Chem Lett. 2017 Oct 15;27(20):4755-4759. doi: 10.1016/j.bmcl.2017.08.052. Epub 2017 Aug 24.

Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1.

Author information

1
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: Daniel.mould@cruk.manchester.ac.uk.
2
Beactica AB, Uppsala Business Park, Virdings allé 2, 75450 Uppsala, Sweden.
3
Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
4
Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.

Abstract

As part of our ongoing efforts to develop reversible inhibitors of LSD1, we identified a series of 4-(pyrrolidin-3-yl)benzonitrile derivatives that act as successful scaffold-hops of the literature inhibitor GSK-690. The most active compound, 21g, demonstrated a Kd value of 22nM and a biochemical IC50 of 57nM. In addition, this compound displayed improved selectivity over the hERG ion channel compared to GSK-690, and no activity against the related enzymes MAO-A and B. In human THP-1 acute myeloid leukaemia cells, 21g was found to increase the expression of the surrogate cellular biomarker CD86. This work further demonstrates the versatility of scaffold-hopping asa method to develop structurally diverse, potent inhibitors of LSD1.

KEYWORDS:

Acute myeloid leukaemia; Cancer therapy; Epigenetic therapy; Epigenetics; KDM1A; LSD1; Reversible inhibitor; Stem cell differentiation

PMID:
28927796
DOI:
10.1016/j.bmcl.2017.08.052
[Indexed for MEDLINE]

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