Tetrazolylhydrazides as Selective Fragment-Like Inhibitors of the JumonjiC-Domain-Containing Histone Demethylase KDM4A.
The JumonjiC-domain-containing histone demethylase 2A (JMJD2A, KDM4A) is a key player in the epigenetic regulation of gene expression. Previous publications have shown that both elevated and lowered enzyme levels are associated with certain types of cancer, and therefore the definite role of KDM4A in oncogenesis remains elusive. To identify a novel molecular starting point with favorable physicochemical properties for the investigation of the physiological role of KDM4A, we screened a number of molecules bearing an iron-chelating moiety by using two independent assays. In this way, we were able to identify 2-(1H-tetrazol-5-yl)acetohydrazide as a novel fragment-like lead structure with low relative molecular mass (Mr =142 Da), low complexity, and an IC50 value of 46.6 μm in a formaldehyde dehydrogenase (FDH)-coupled assay and 2.4 μm in an antibody-based assay. Despite its small size, relative selectivity against two other demethylases could be demonstrated for this compound. This is the first example of a tetrazole group as a warhead in JMJD demethylases.
Institute of Pharmacy, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17487, Greifswald, Germany.
Nicole
N
Rüger
Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
Martin
M
Roatsch
Institute of Pharmacy, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17487, Greifswald, Germany.
Thomas
T
Emmrich
University of Freiburg Medical Center, Department of Urology, Women's Hospital and Center for Clinical Research, Breisacher Str. 66, 79106, Freiburg, Germany.
Henriette
H
Franz
University of Freiburg Medical Center, Department of Urology, Women's Hospital and Center for Clinical Research, Breisacher Str. 66, 79106, Freiburg, Germany.
Roland
R
Schüle
Institute of Pharmaceutical Sciences, Albert-Ludwigs-Universität Freiburg, Albertstr. 25, 79104, Freiburg, Germany.
Manfred
M
Jung
Institute of Pharmacy, Ernst-Moritz-Arndt-Universität Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17487, Greifswald, Germany. Link@uni-greifswald.de.
Andreas
A
Link
D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D006834:Hydrazines; D013777:Tetrazoles; D056484:Jumonji Domain-Containing Histone Demethylases; C494424:KDM4A protein, human
acyl hydrazides; acyl hydrazones; epigenetics; histone demethylase; tetrazoles