Chemistry

Scientists discover chemical probe for previously ‘untreatable’ cancer target

Structural models predict that the small molecule binding site on FOXA1 is close to DNA. Credit: Scripps Research

Cancers caused by hormones, such as breast and prostate cancers, often rely on a difficult-to-target protein called forkhead box protein 1 (FOXA1). FOXA1 mutations may enable these types of cancers to grow and proliferate. Currently, FOXA1 is notoriously difficult to block with drugs, but that may soon change.

Scientists at the Scripps Research Institute have identified a key binding site on FOXA1 that could pave the way for future cancer treatments. The team’s findings, published in the journal Molecular Cell on October 15, 2024, also reveal how small drug-like compounds, called small molecules, interact with proteins.

While studying protein interactions on a large scale, researchers in the lab of co-corresponding author and Norton B. Gilula Professor of Biology and Chemistry Benjamin Cravat, Ph.D., found that small molecules do indeed interact with FOXA1. I discovered that it is possible.

“FOXA1 was historically thought to be untreatable,” Cravat says. “This protein is thought to lack the kind of surface that small molecule drugs can bind to, which is probably why it has been so difficult to target this protein.”

Following that discovery, Cravatt’s lab collaborated with Dr. Michael Erb’s lab to better understand how these molecules affect FOXA1 function.

Both Cravat and Erb used two forms of activity-based protein profiling (ABPP). ABPP is a technology pioneered by Cravat’s lab to capture protein activity on a global scale. This dual approach not only allowed us to determine whether a small molecule could bind to FOAX1, but also to identify the exact binding site.

Erb and his group are particularly interested in how certain genes are turned “on” or “off” by proteins called transcription factors, and how this triggers the cellular conditions that lead to cancer. I’m interested. Transcription factors, such as FOXA1, bind to specific regions of DNA and control whether genes are activated (turned “on”) or repressed (turned “off”). This regulation is essential to how cells function and respond to change. For example, in hormone-driven cancers that often rely on FOXA1 to grow.

“FOXA1 is what is called a master regulator of gene regulation, or lineage determinant,” says Erb, co-corresponding author of the study and associate professor in the Department of Chemistry. “We discovered a specific site on FOXA1 that can bind small molecules. This is because transcription factors like FOXA1 are attractive targets not only for cancer but also for many other diseases. is a very important discovery.”

This finding was unexpected because it is very rare to find small molecule binding sites on transcription factors.

“A common analogy is that drugs bind to proteins like a key in a lock, but the common analogy is that most transcription factors do not have binding sites to unlock them. It’s a mindset,” Erb added. “FOXA1’s binding site is like a hidden lock. It’s hard to imagine how we could have discovered it without the ABPP technology that exists today.”

Another surprising finding is that FOXA1 normally binds to different sequences of DNA bases to control gene regulation, but when FOXA1 binds to a small molecule, its preferred sequence changes, causing the protein to behave normally. will be able to target different genes.

This discovery may help future researchers understand how such molecules affect gene regulation in cancer. If small molecules alter FOXA1’s DNA preferences, they can affect which genes are turned on or off, potentially affecting cancer growth.

“We found that small molecules can affect FOXA1’s ability to interpret information written into the genome,” Erb said.

Additionally, the researchers found that certain mutations in FOXA1 affect regions close to where small molecules might bind to proteins. These mutations changed the way FOXA1 interacted with DNA, in exactly the same way as small molecules.

“This suggests that hotspots for cancer-associated mutations are also hotspots for small molecule binding events,” Erb points out.

The researchers found that, contrary to initial belief, small molecules cannot bind to FOXA1 on their own. Instead, it can only bind to FOXA1 if the protein is already bound to a DNA sequence. Thus, the effectiveness of small molecules in cancer treatment likely depends on the interaction of FOXA1 and DNA.

Looking forward, Erb and Cravat will explore optimizing FOXA1 ligands as antagonists of their function and cancer growth, as well as using ABPP to target FOXA1, which is currently considered undruggable. We plan to explore small molecule binding sites on other transcription factors.

“Now that we have created a chemical probe to study FOXA1, we hope that our work will stimulate the development of drugs that target this protein,” says Cravat.

In addition to Cravatt and Erb, the study’s authors include Junwon Sang, Yuxian Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. McRae, and Kristen They include Mr. E. Demeester, Mr. Evert Nyomen, Mr. Jarrett R. Remsberg, and Mr. Bruno Melillo. Scripps Research.

More information: Sang Joong-won et al. Redirecting the pioneering function of FOXA1 with covalent small molecules, Molecular Cell (2024). DOI: 10.1016/j.molcel.2024.09.024. www.cell.com/molecular-cell/fu … 1097-2765(24)00780-9

Provided by Scripps Research Institute

Citation: Scientists discover chemical probe for previously ‘untreatable’ cancer target (October 15, 2024) https://phys.org/news/2024-10-scientists-chemical- Retrieved October 15, 2024 from probes-previously-undruggable.html

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