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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:27

Article

Mould, Daniel P.¹  Bremberg, Ulf³  Jordan, Allan M.¹  Geitmann, Matthis³  McGonagle, Alison E.¹  Somervaille, Tim C. P.²  Spencer, Gary J.²  Ogilvie, Donald J.¹ 

[1] Univ Manchester, Canc Res UK Manchester Inst, Drug Discovery Unit, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[2] Univ Manchester, Canc Res UK Manchester Inst, Leukaemia Biol Lab, Wilmslow Rd, Manchester M20 4BX, Lancs, England

[3] Beactica AB, Uppsala Business Pk,Virdings Alle 2, S-75450 Uppsala, Sweden

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

DOI  :  10.1016/j.bmcl.2017.08.052

来源: Elsevier

【 摘 要 】

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 K-d 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. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

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