Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1 |
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| Authors: | Daniel P Mould Ulf Bremberg Allan M Jordan Matthis Geitmann Alison E McGonagle Tim CP Somervaille Gary J Spencer Donald J Ogilvie |
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| Institution: | 1. Drug Discovery Unit, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK;2. Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK;3. Beactica AB, Uppsala Business Park, Virdings allé 2, 75450 Uppsala, Sweden |
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| 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 22 nM and a biochemical IC50 of 57 nM. 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 as a method to develop structurally diverse, potent inhibitors of LSD1. |
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| Keywords: | Epigenetics LSD1 KDM1A Reversible inhibitor Stem cell differentiation Cancer therapy Epigenetic therapy Acute myeloid leukaemia |
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