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Tetrazolylhydrazides as Selective Fragment‐Like Inhibitors of the JumonjiC‐Domain‐Containing Histone Demethylase KDM4A
Author(s) -
Rüger Nicole,
Roatsch Martin,
Emmrich Thomas,
Franz Henriette,
Schüle Roland,
Jung Manfred,
Link Andreas
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201500335
Subject(s) - demethylase , chemistry , epigenetics , histone , biochemistry , stereochemistry , gene
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‐(1 H ‐tetrazol‐5‐yl)acetohydrazide as a novel fragment‐like lead structure with low relative molecular mass ( M r =142 Da), low complexity, and an IC 50 value of 46.6 μ m in a formaldehyde dehydrogenase (FDH)‐coupled assay and 2.4 μ m 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.