Chemists at the University of Hong Kong have designed a first-in-class drug that shuts down a key epigenetic complex in lung cancer cells, sharply slowing tumor growth in lab and animal studies. The work could open the door to a new generation of highly selective cancer therapies.
A team of chemists at the University of Hong Kong has developed a first-in-class drug that shuts down a critical epigenetic regulator in lung cancer cells, offering a new strategy to tackle one of the world’s deadliest cancers.
Working with collaborators in mainland China, the researchers designed a highly selective inhibitor that targets the ATAC complex, a molecular “switch operator” that helps turn cancer-driving genes on. In cell and animal studies of non-small cell lung cancer, the compound sharply reduced tumor growth and spread.
The research, published in Nature Chemical Biology, also lays out a blueprint for designing similarly precise drugs against other disease-related gene control systems.
Inside every human cell, long strands of DNA are wrapped around proteins called histones, forming a structure known as chromatin. Chemical tags added to histones act like switches, helping determine which genes are active and which stay silent. One of the most important of these tags is histone acetylation, which generally turns genes “on” by loosening chromatin and making DNA more accessible.
Enzyme complexes called histone acetyltransferases, or HATs, add these acetyl tags. The ATAC complex is one such HAT complex. It plays a central role in activating genes involved in cell growth and DNA replication.
In cancers such as non-small cell lung cancer, ATAC becomes overactive. That overactivity flips the “on” switch for many cancer-promoting genes, driving uncontrolled tumor growth and metastasis. Blocking ATAC has long been an attractive idea, but it has proved difficult to do without also disrupting other HAT complexes that share key components and are essential for normal cell function.
Earlier drug efforts focused on GCN5, the catalytic engine that carries out histone acetylation within ATAC. The problem is that GCN5 is reused in several different HAT complexes. Inhibiting it broadly risks serious side effects because it would interfere with many normal gene programs, not just those fueling tumors.
To get around this, the research team took a different route. Instead of going after the shared catalytic core, they targeted YEATS2, a protein subunit that is unique to the ATAC complex.
Using structure-guided drug design, the researchers created a small molecule, called LS-170, that binds tightly and specifically to the acetyl-lysine recognition domain of YEATS2. That domain normally helps anchor the ATAC complex to chromatin at particular spots in the genome.
When LS-170 binds YEATS2, it blocks that recognition site. As a result, ATAC is displaced from its usual genomic targets. Local histone acetylation levels drop, and key cancer-driving genes in non-small cell lung cancer cells are switched off.
In lab-grown lung cancer cell lines, LS-170 showed strong anti-tumor activity. In animal models, treatment with the compound significantly reduced tumor volume and suppressed metastasis, demonstrating its potential as an anti-cancer agent.
The implications may extend beyond lung cancer. The YEATS2 gene is frequently amplified in several solid tumors, including lung, ovarian and pancreatic cancers. That pattern suggests that drugs like LS-170, which are tuned to YEATS2 and the ATAC complex, could eventually be useful across multiple cancer types where this pathway is overactive.
Beyond its therapeutic promise, the study also provides a powerful research tool. By selectively disabling ATAC without touching other HAT complexes, scientists can more clearly map out what this single complex does in cancer cells and in normal biology. The authors describe their work as the first chemical approach to precisely decode the function of a specific HAT complex.
The project was about more than just making a potent drug candidate, according to co-corresponding author Xiang David Li, a professor in HKU’s Department of Chemistry.
“In this work, we didn’t just create a potent and highly specific inhibitor that can suppress tumours, we also uncovered a novel strategy to target just one epigenetic complex out of several that share the same enzyme core. This approach opens up exciting possibilities for developing highly selective, complex-specific drugs that could potentially revolutionise treatments for human diseases,” he said in a news release.
That strategy — focusing on complex-specific subunits like YEATS2 rather than shared catalytic engines — could help drug developers design medicines that are both effective and far more precise. In cancer and other diseases driven by misregulated gene expression, such precision could reduce side effects by sparing healthy gene programs while shutting down harmful ones.
The research was an interdisciplinary effort led by Li in HKU’s Department of Chemistry, together with Weiping Wang, an associate professor in HKU’s Department of Pharmacology and Pharmacy; Xin Li, a researcher at Shenzhen Bay Laboratory; and Haitao Li, a professor in the School of Basic Medical Sciences at Tsinghua University. The team has filed multiple international patent applications related to LS-170 and the underlying approach.
While LS-170 is still at an early, experimental stage, the findings point to a new class of epigenetic therapies that act not as blunt instruments, but as finely tuned tools. The next steps will likely include more detailed safety studies, optimization of the compound and exploration of its effects in additional cancer models.
If those efforts succeed, the same design principles could be applied to other epigenetic complexes, potentially opening a broader pipeline of complex-specific drugs aimed at cancer and a range of other human diseases.
Source: University of Hong Kong