Development and evaluation of 4-(pyrrolidin-3-yl)benzonitrile derivatives as inhibitors of lysine specific demethylase 1. Issue 20 (15th October 2017)

• Record Type: Journal Article
• Authors: Mould, Daniel P.; Bremberg, Ulf; Jordan, Allan M.; Geitmann, Matthis; McGonagle, Alison E.; Somervaille, Tim C.P.; Spencer, Gary J.; Ogilvie, Donald J.
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 20(2017)
• Page Start: 4755
• Page End: 4759
• Publication Date: 2017-10-15
• Subjects: Epigenetics -- LSD1 -- KDM1A -- Reversible inhibitor -- Stem cell differentiation -- Cancer therapy -- Epigenetic therapy -- Acute myeloid leukaemia; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.08.052
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 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.