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.

Tetrazoles are small functional heterocycles that are suited to serve simultaneously as aromatic platform for diversity and as functional interaction motif. Furthermore, the tetrazole ring and its deprotonated tetrazolate counterpart are metal ion complexing ligands that possess a rich variety of binding and bridging modes. We recently demonstrated that fragments containing the tetrazole moiety and a metal chelating hydrazide group are well suited to discover selective screening hits with high ligand efficiency for a given protein target. Here, we report the synthesis and characterization of new polydentate tetrazole-containing screening compounds and their synthetic precursors as well as their deposition in a multipurpose screening library in the frame of the EU-OPENSCREEN network. The pure and well-characterized screening compounds could be useful to aid drug discovery programs for multiple or hitherto undruggable targets by enclosure of under-represented tetrazole derivatives.

Human histone demethylases are known to play an important role in the development of several tumor types. Consequently, they have emerged as important medical targets for the treatment of human cancer. Herein, structural studies on tetrazolylhydrazide inhibitors as a new scaffold for a certain class of histone demethylases, the JmjC proteins, are reported. A series of compounds are structurally described and their respective binding modes to the KDM4D protein, which serves as a high‐resolution model to represent the KDM4 subfamily in crystallographic studies, are examined. Similar to previously reported inhibitors, the compounds described herein are competitors for the natural KDM4 cofactor, 2‐oxoglutarate. The tetrazolylhydrazide scaffold fills an important gap in KDM4 inhibition and newly described, detailed interactions of inhibitor moieties pave the way to the development of compounds with high target‐binding affinity and increased membrane permeability, at the same time.

The inside cover picture shows a cross‐sectional view of histone lysine demethylase 4A (KDM4A) with a trimethylated histone fragment and 2‐oxoglutarate, its substrate and cosubstrate, respectively, bound to the active center. Previous publications indicate the ambiguous involvement of this enzyme in oncogenesis. We prepared small, fragment‐like tetrazole derivatives that bear a metal‐chelating acylhydrazide warhead and are able to competitively inhibit this key player in the epigenetic regulation of gene expression. Relative selectivity for KDM4A over related demethylases could be demonstrated. More details can be found in the Full Paper by Andreas Link et al. on page 1875 in Issue 11, 2015 (DOI: 10.1002/cmdc.201500335).

The Front Cover highlights the modus operandi of the structure‐based screening of the described tetrazole hydrazide compounds vs. human histone methyltransferase (KDM4D). The compounds were soaked one by one into the protein crystals, and the corresponding structures revealed the binding of the receptive compounds in the protein's active site. Both hydrazide and tetrazole warheads were identified as strong binding motifs. The structural information on the binding of the compounds will form the basis for further compound development towards KDM4D inhibitor identification. More information can be found in the Full Paper by Manfred S. Weiss et al. on page 1828 in Issue 21, 2019 (DOI: 10.1002/cmdc.201900441).