# High Throughput Screen for Inhibitors of the YEATS2 Histone Acylation Reader

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $412,895

## Abstract

PROJECT SUMMARY
Lung cancer is the leading cause of cancer-related deaths in both men and women in the U.S and worldwide.
There are more than 400,000 deaths of lung cancer worldwide each year, among which lung squamous cell
carcinoma (LUSC) accounts for about 30%. However, no effective treatments for LUSC are available. LUSC is
one type of non-small cell lung cancer (NSCLC) characterized by numerous DNA alterations, including
frequent amplification of the 3q26 chromosomal segment. The 3q26 segment is noteworthy because it contains
the YEATS domain containing 2 (YEATS2) gene, a gene that is frequently amplified in a number of human
cancers, including LUSC (~50%), ovarian (28%), head and neck (25%), and esophagus cancers (25%). High
YEATS2 mRNA expression is associated with a poor prognosis of NSCLC patients, indicating that YEATS2
may have a tumor-promoting role.
YEATS2 is a stoichiometric subunit of the Ada-Two-A-Containing (ATAC) complex, a conserved metazoan
histone acetyltransferase (HAT) complex. YEATS2 contains an evolutionally conserved YEATS domain. We
previously showed that the YEATS domain of YEATS2 functions as a reader of histone acetylation and other
types of histone acylation such as crotonylation. Importantly, disrupting the YEATS histone reading activity
impairs the normal functions of YEATS2 and the ATAC complex, resulting in reduced histone acetylation,
decreased target gene expression, and inhibition of cell growth and survival of NSCLC. These data
demonstrate that the YEATS domain of YEATS2 is a potential drug target, and that targeting YEATS2 may
provide a therapeutic approach for treating NSCLC and other types of cancer characterized by YEATS2
amplification.
The objective of this proposal is to develop potent and specific inhibitors targeting the histone acylation binding
activity of the YEATS domain of YEATS2. For this, we will (1) conduct a high-throughput screen to identify
YEATS2 small-molecule inhibitors, and (2) evaluate and characterize hit compounds in in vitro and cell-based
assays. Through the proposed studies, we expect to identify potent, specific YEATS2 YEATS domain chemical
probes of different chemotypes. These compounds will provide the basis for further development of small
molecules for targeted therapies. Likewise, the research community will be able to use these new inhibitors as
important tools to understand the functions and mechanisms of YEATS2 in human cancers.

## Key facts

- **NIH application ID:** 10749894
- **Project number:** 5R01CA268440-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Xiaobing Shi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $412,895
- **Award type:** 5
- **Project period:** 2022-01-14 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10749894

## Citation

> US National Institutes of Health, RePORTER application 10749894, High Throughput Screen for Inhibitors of the YEATS2 Histone Acylation Reader (5R01CA268440-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10749894. Licensed CC0.

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