Glioma-amplified sequence 41 (<i>GAS41</i>) is an oncogene overexpressed in multiple cancers including brain, colorectal, and non-small cell lung cancers (NSCLC). GAS41 protein contains a YEATS domain, a subtype of epigenetic reader domains that recognize lysine residues on histone proteins that have been post-translationally modified with acetyl groups. GAS41 preferentially recognizes acetylated and crotonylated histone H3 lysine 27 residues, and this reader activity recruits GAS41 to the promoters of actively transcribed genes. Genetic approaches validated the role of the YEATS domain of GAS41 in oncogenesis in NSCLC, suggesting that disrupting GAS41 YEATS domain chromatin recognition might represent an attractive target for development of small molecule inhibitors. Using the NMR-based fragment screening combined with medicinal chemistry optimization, we identified and developed small molecule inhibitors of the GAS41 YEATS domain. Using protein X-ray crystallography, we were able to obtain high resolution crystal structures of both the peptide H3K27ac and a fragment-derived inhibitor bound to GAS41 to further guide medicinal chemistry efforts. Biochemical assays with GAS41 and other YEATS domain-containing proteins showed that these inhibitors are potent and highly selective for GAS41. We have also shown that our lead compounds inhibit NSCLC cell proliferation, engage and stabilize GAS41 protein in cells, and significantly alter expression of NSCLC-related genes. This work reports the first-in-class small-molecule inhibitors of the GAS41 YEATS domain reported to date and provides a promising scaffold for further optimization to identify new targeted therapy for NSCLC.

Development of small-molecule inhibitors of GAS41 histone reader protein

ACS Spring 2022

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