Development of potent dimeric inhibitors of GAS41 YEATS domain

GAS41 is an emerging oncogene overexpressed and implicated in multiple cancers, including non-small cell lung cancer (NSCLC). GAS41 is a dimeric protein that contains the YEATS domain, which is involved in the recognition of lysine-acylated histones. Here, we report the development of GAS41 YEATS inhibitors by employing a fragment-based screening approach. These inhibitors bind to GAS41 YEATS domain in a channel constituting a recognition site for acylated lysine on histone proteins. To enhance inhibitory activity, we developed a dimeric analog with nanomolar activity that blocks interactions of GAS41 with acetylated histone H3. Our lead compound engages GAS41 in cells, blocks proliferation of NSCLC cells, and modulates expression of GAS41-dependent genes, validating on-target mechanism of action. This study demonstrates that disruption of GAS41 protein-protein interactions may represent an attractive approach to target lung cancer cells. This work exemplifies the use of bivalent inhibitors as a general strategy to block challenging protein-protein interactions. [Display omitted] •Thiophene amide class of compounds binds selectively to GAS41 YEATS domain•GAS41 inhibitors bind into a channel involved in recognition of acylated lysine•Bivalent analogs have significantly enhanced activity over monomeric inhibitors•Lead compound demonstrates on-target inhibition of GAS41 in cancer cells By employing a fragment screening approach, Listunov et al. developed small molecule inhibitors of GAS41 YEATS domain. They found that dimeric GAS41 inhibitors have significantly enhanced potency over monomeric inhibitors, engage GAS41 in cells, and inhibit growth of lung cancer cells.