JHDMs (JmjC-domain-containing histone demethylases) are the largest class of demethylase enzymes, contain a Jumonji C (JmjC) domain and catalyze lysine demethylation of histones through an oxidative reaction that requires Fe(II) ion and α-ketoglutarate (αkG) as cofactors. The misregulation of these enzymes, in particular JMJD2 subfamily, has being significantly implicated in cancer initiation and progression. Potent and specific inhibitors of these enzymes have not been identified yet. Moreover, most of the reported ones show a good affinity to many other Fe(II)/αkG dependent oxygenases, are non-specific for the different isoforms or are affected by undesirable characteristics. By means of an high throughput screening (HTS) campaign, we selected a pool of interesting hit compounds and then, to refine the results, filtered out poor quality scaffolds not suitable for future optimization. The use of a multiple combined approach of different in vitro techniques led us to select EML586 as scaffold for further derivatization. From a series of EML586 analogues we were able to derive a pharmacophore hypothesis and structure-activity relationships (hit-to-lead), and to select 3-hydroxy-2,3-dihydroquinazolinone moiety as starting point for the development of novel optimized derivatives. The substitution of quinoxaline ring with more aliphatic portions gave derivatives such as EML678 and EML684, which demonstrate a better activity against hKDM4A compared to the starting hit compound (Figure 1). Furthermore, they induced a marked reduction in methylation of lysines H3K9 and H3K27 in a cell-based assay together with an arrest in the S-phase of cell cycle.
|Titolo:||Identification of new KDM4 inhibitors through a HTS and hit refinement strategy|
SBARDELLA, Gianluca (Corresponding)
|Data di pubblicazione:||2017|
|Appare nelle tipologie:||4.3 Poster|