Development of potent dimeric inhibitors of GAS41 YEATS domain
Dymytrii Listunov1, Brian M Linhares1, EunGi Kim1
1Department of Pathology, University of Michigan, 1150 West Medical Center Dr, MSRB I, Room 4510D, Ann Arbor, MI 48108, USA.
Abstract:
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.
Insights
Researchers developed novel inhibitors targeting the GAS41 protein, an oncogene implicated in non-small cell lung cancer (NSCLC). These inhibitors block GAS41
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Growth-arrest specific 41 (GAS41) is an emerging oncogene.
- GAS41 overexpression is linked to various cancers, notably non-small cell lung cancer (NSCLC).
- GAS41 possesses a YEATS domain crucial for recognizing lysine-acylated histones.
Purpose of the Study:
- To develop inhibitors targeting the GAS41 YEATS domain.
- To investigate the potential of disrupting GAS41 protein-protein interactions for cancer therapy.
- To validate the on-target mechanism of action for novel GAS41 inhibitors in NSCLC cells.
Main Methods:
- Fragment-based screening approach to identify GAS41 YEATS inhibitors.
- Development of a dimeric analog to enhance inhibitory activity.
- Cell-based assays to assess compound engagement, proliferation inhibition, and gene expression modulation.
Main Results:
- Identified inhibitors that bind to the GAS41 YEATS domain, specifically within the acylated lysine recognition site.
- Developed a dimeric inhibitor with nanomolar activity that effectively blocks GAS41 interaction with acetylated histone H3.
- Demonstrated that the lead compound engages GAS41 in cells, inhibits NSCLC cell proliferation, and alters GAS41-dependent gene expression.
Conclusions:
- Disrupting GAS41 protein-protein interactions is a promising therapeutic strategy for NSCLC.
- Bivalent inhibitors represent a viable approach for targeting challenging protein-protein interactions.
- The developed GAS41 inhibitors offer a potential new avenue for NSCLC treatment.
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