Development of 5-hydroxypyrazole derivatives as reversible 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  Maiques-Diaz, Alba²  McGonagle, Alison E.¹  Small, Helen F.¹  Somervaille, Tim C. P.²  Ogilvie, Donald¹ 

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

[2] Univ Manchester, Leukaemia Biol Grp, Canc Res UK Manchester Inst, 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.2017.05.018

来源: Elsevier

【 摘 要 】

A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23 mu M. Optimisation of this compound by rational design afforded compounds with K-d values of <10 nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound. (C) 2017 Elsevier Ltd. All rights reserved.

【 授权许可】

Free