Discovery and Development of a Small-Molecule Inhibitor Targeting the GAS41 YEATS Domain in Nonsmall Cell Lung Cancer

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 DLG-41, a submicromolar inhibitor binding to the GAS41 YEATS
domain. DLG-41 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. DLG-41 induces more
effective growth inhibition in A549 versus GAS41-knockout cells, demonstrating
on-target activity. DLG-41 treatment upregulates the CDKN1A gene and downregulates pathways associated with lung
cancer cell identity, tumor migration, and invasion. DLG-41 is a promising chemical probe for targeting GAS41 protein in NSCLC
models and has potential for future development.