9O4Y

GAS41 YEATS domain in complex with DLG-1

This is a non-PDB format compatible entry.

Summary for 9O4Y

• Entry DOI: 10.2210/pdb9o4y/pdb
• Descriptor: YEATS domain-containing protein 4, DI(HYDROXYETHYL)ETHER, SULFATE ION, ... (5 entities in total)
• Functional Keywords: inhibitor, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 4
• Total formula weight: 73750.03

Authors

Clegg, B.D.,Winkler, A.,Linhares, B.M.,Cierpicki, T.,Grembecka, J. (deposition date: 2025-04-09, release date: 2026-02-25, Last modification date: 2026-03-04)

Primary citation

Listunov, D.,Winkler, A.,Ray, J.,Linhares, B.M.,Clegg, B.,Weaver, S.,Kim, E.,Zari, S.,Park, S.R.,Zolov, S.N.,Chuikov, S.,Zhao, L.,Shah, Y.M.,Keshamouni, V.G.,Grembecka, J.,Cierpicki, T.
Discovery and Development of a Small-Molecule Inhibitor Targeting the GAS41 YEATS Domain in Nonsmall Cell Lung Cancer.
J.Med.Chem., 68:25324-25351, 2025

PubMed Abstract: GAS41 is frequently overexpressed in Non-Small Cell Lung Cancer (NSCLC). GAS41 contains a YEATS domain, which recognizes acetylated lysine residues on histones to recruit protein complexes and facilitate transcription. Suppression of GAS41 in NSCLC models inhibits cellular proliferation and markedly reduces tumor growth in mouse xenografts, justifying the development of small-molecule inhibitors. We have employed structure-based design and medicinal chemistry optimization to discover , a submicromolar inhibitor binding to the GAS41 YEATS domain. potently disrupts the association of GAS41 YEATS with chromatin in mammalian cells and inhibits the proliferation of NSCLC cell lines with submicromolar potency without significantly affecting normal lung fibroblasts. induces more effective growth inhibition in A549 versus GAS41-knockout cells, demonstrating on-target activity. treatment upregulates the gene and downregulates pathways associated with lung cancer cell identity, tumor migration, and invasion. is a promising chemical probe for targeting GAS41 protein in NSCLC models and has potential for future development.

PubMed: 41294372
DOI: 10.1021/acs.jmedchem.5c02307

Experimental method

X-RAY DIFFRACTION (2.3 Å)