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. Anchor fragment: To develop non‐promiscuous metalloenzyme inhibitors, a metal‐complexing acetohydrazide group was integrated in a tetrazolyl fragment, which can be matured into a scaffold to promote further selectivity at the ligand backbone binding site of these emerging drug targets.