Dynamic combinatorial chemistry (DCC) is a powerful supramolecular approach for discovering ligands for biomolecules. To date, most, if not all, biologically templated DCC systems employ only a single biomolecule to direct the self-assembly process. To expand the scope of DCC, herein, a novel multiprotein DCC strategy has been developed that combines the discriminatory power of a zwitterionic "thermal tag" with the sensitivity of differential scanning fluorimetry. This strategy is highly sensitive and could differentiate the binding of ligands to structurally similar subfamily members. Through this strategy, it was possible to simultaneously identify subfamily-selective probes against two clinically important epigenetic enzymes: FTO (7; IC =2.6 μm) and ALKBH3 (8; IC =3.7 μm). To date, this is the first report of a subfamily-selective ALKBH3 inhibitor. The developed strategy could, in principle, be adapted to a broad range of proteins; thus it is of broad scientific interest.

A dynamic biosensor which switches conformation according to its methylation status enables highly sensitive detection of m6A-demethylase activity. This strategy may be adapted to a broad range of RNA-modifying enzymes.

We describe a novel methylation-sensitive nucleic acid (RNA) probe which switches conformation according to its methylation status. When combined with a differential scanning fluorimetry technique, it enables highly sensitive and selective detection of demethylase activity at a single methylated-base level. The approach is highly versatile and may be adapted to a broad range of RNA demethylases.

A multi‐protein differential scanning fluorimetry (DSF) strategy is reported. This strategy uses a thermal tag to exclusively fine‐tune the melting temperature of the target proteins such that their individual melting profiles could be monitored in a single DSF melting analysis. When combined with dynamic combinatorial chemistry, formation of protein–ligand complexes can be detected by shifts in Tm of proteins engaged in ligand binding. This strategy led to the simultaneous discovery of selective ligands for two epigenetic enzymes, FTO and ALKBH3. More information can be found in the Full Paper by Esther C. Y. Woon et al. on page 2854 in Issue 19, 2018 (DOI: 10.1002/asia.201800729). Graphic design: Rachel Lim Si Hui.