Discovery of a Highly Selective Cell-Active Inhibitor of the Histone Lysine Demethylases KDM2/7.

Authors :: Gerken PA
Wolstenhulme JR
Tumber A
Hatch SB
Zhang Y
Müller S
Chandler SA
Mair B
Li F
Nijman SMB
Konietzny R
Szommer T
Yapp C
Fedorov O
Benesch JLP
Vedadi M
Kessler BM
Kawamura A
Brennan PE
Smith MD
Source :: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2017 Dec 04; Vol. 56 (49), pp. 15555-15559. Date of Electronic Publication: 2017 Nov 07.
Publication Year :: 2017
Abstract: Histone lysine demethylases (KDMs) are of critical importance in the epigenetic regulation of gene expression, yet there are few selective, cell-permeable inhibitors or suitable tool compounds for these enzymes. We describe the discovery of a new class of inhibitor that is highly potent towards the histone lysine demethylases KDM2A/7A. A modular synthetic approach was used to explore the chemical space and accelerate the investigation of key structure-activity relationships, leading to the development of a small molecule with around 75-fold selectivity towards KDM2A/7A versus other KDMs, as well as cellular activity at low micromolar concentrations.<br /> (© 2017 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.)

Subjects :: Dose-Response Relationship, Drug
Enzyme Inhibitors chemical synthesis
Enzyme Inhibitors chemistry
F-Box Proteins metabolism
HeLa Cells
Humans
Jumonji Domain-Containing Histone Demethylases metabolism
Molecular Structure
Structure-Activity Relationship
Drug Discovery
Enzyme Inhibitors pharmacology
F-Box Proteins antagonists & inhibitors
Jumonji Domain-Containing Histone Demethylases antagonists & inhibitors

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