DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF NOVEL G9A INHIBITORS FROM A SCAFFOLD HOPPING APPROACH

The lysine methyltransferase G9a (also named euchromatin histone methyltransferase 2, EHMT2) is primarily responsible for the dimethylation of lysine 9 on histone H3 (H3K9). Several reports have highlighted its link to a variety of cancers. In particular, it has been shown that G9a is crucial for the oncogenic role of the repressor element (RE)-1 silencing transcription factor (REST) in the pediatric brain tumor medulloblastoma. Only a few among the selective inhibitors of G9a reported to date are useful chemical probes for cell-based and animal studies. Starting from the inhibitor UNC0638,3 we applied a scaffold hopping approach to develop novel chemical entities endowed with high affinity towards the G9a. In particular, we replaced the quinazoline core, typical of most of the reported inhibitors, with 1,4-benzodiazepine nucleus, known to be a privileged structure. We chose the 3,4-dihydro-5H-benzo[e][1,4]diazepin-5-one scaffold, that can be obtained through an efficient and gram-scale continuous-flow protocol, previously optimized by our group.4 Moreover, this scaffold could be easily decorated to provide a number of highly functionalized potential ligands. To validate our approach, we designed and synthesized a small library of UNC0638 analogues. All the compounds were tested through a peptide-based AlphaLISA, measuring the levels of H3K9 dimethylation.