October 15, 2024
16/10/2024
October 15, 2024
LA JOLLA, CA Hormone-driven cancers, like those of the breast and prostate, often rely on a tricky-to-target protein called Forkhead box protein 1 (FOXA1). FOXA1 mutations can enable these types of cancers to grow and proliferate. Today, FOXA1 is notoriously difficult to block with drugs but that may soon change.
Scripps Research scientists have identified a crucial binding site on FOXA1 that could pave the way for future cancer treatments. The team's findings, which were published in Molecular Cell on October 15, 2024, also mapped out how tiny drug-like chemical compounds called small molecules interact with the protein.
While examining protein interactions on a large scale, investigators in the lab of co-corresponding author Benjamin Cravatt, PhD, the Norton B. Gilula Chair in Biology and Chemistry, determined that small molecules could, in fact, interact with FOXA1.
FOXA1 had historically been considered undruggable, says Cravatt. It's thought to lack the types of surfaces that small molecule drugs can bind to, which is likely why it's been so difficult to target the protein.
Following its discovery, Cravatt's lab teamed up with the lab of Michael Erb, PhD, to better understand how those molecules might affect the functions of FOXA1.
Both Cravatt and Erb used two forms of activity-based protein profiling (ABPP), a technique that Cravatt's lab pioneered to capture protein activity on a global scale. The dual approach allowed them not only to determine whether a small molecule could bind to FOAX1 at all, but also to pinpoint the exact binding site.
Erb and his group are particularly interested in how certain genes are turned on and off by proteins called transcription factors, and how this leads to cell states that cause cancer. Transcription factors like FOXA1 bind to specific regions of DNA and control whether a gene is activated (turned on ) or repressed (turned off ). This regulation is essential to how cells function and respond to changes such as in the case of hormone-driven cancers, which often depend on FOXA1 to grow.
FOXA1 is a master regulator of gene control, or what we call a lineage-defining factor, says Erb, the study's co-corresponding author and an associate professor in the Department of Chemistry. We found a specific site on FOXA1 that can bind to small molecules, which is a tremendously important discovery since transcription factors like FOXA1 are not only attractive targets for cancer, but also many other diseases.
Because it's so rare to find a small molecule binding site on a transcription factor, the discovery was unexpected.
A common analogy is that drugs bind to proteins like keys inside a lock, but the prevailing attitude is that most transcription factors don't have binding sites to unlock, adds Erb. The binding site on FOXA1 is like a hidden lock; without the ABPP technology as it exists today, it's hard to imagine how we would have discovered it.
Another surprising finding: FOXA1 usually binds to a distinct sequence of DNA bases to control gene regulation but binding FOXA1 to small molecules changed the sequences that it preferred, allowing the protein to target different genes than it normally would.
This discovery may help future researchers understand how such molecules affect gene regulation in cancer. If small molecules alter FOXA1's DNA preferences, they could influence which genes are turned on or off potentially affecting cancer growth.
We found small molecules could impact FOXA1's ability to interpret the information written into the genome, says Erb.
Furthermore, the team determined that certain mutations in FOXA1 affected areas close to where small molecules could attach to the protein. These mutations changed how FOXA1 interacted with DNA in the exact same way that the small molecules did.
This suggests that a hotspot for cancer-associated mutations is also a hotspot for small molecule binding events, points out Erb.
Contrary to what they originally thought, the researchers found that small molecules couldn't just attach to FOXA1 on their own. Instead, they could only bind to FOXA1 when the protein was already bound to DNA sequences meaning the effectiveness of small molecules as cancer treatments probably relies on FOXA1's interactions with DNA.
Looking ahead, Erb and Cravatt plan to explore the optimization of FOXA1 ligands into antagonists of its function and cancer growth, as well as to use ABPP to search for small molecule binding sites on transcription factors beyond FOXA1 that are currently considered undruggable.
Now that we've created chemical probes to study FOXA1, we hope our research inspires the development of drugs that can target the protein, says Cravatt.
In addition to Cravatt and Erb, authors of the study, Redirecting the pioneering function of FOXA1 with covalent small molecules, include Sang Joon Won, Yuxiang Zhang, Christopher J. Reinhardt, Lauren M. Hargis, Nicole S. MacRae, Kristen E. DeMeester, Evert Njomen, Jarrett R. Remsberg and Bruno Melillo of Scripps Research.
This work was supported by funding from the Howard Hughes Medical Institute Hanna H. Gray Fellowship (GT15176); the Jane Coffin Childs Memorial Fellowship; the National Institutes of Health (F32 CA265211, R35 CA231991, DP5-OD26380 and 1R01CA280720-01A1); and the Ono Pharma Breakthrough Science Initiative Awards Program.
Cancer Cravatt, Benjamin
LINK: | https://www.scripps.edu/news-and-events/press-room/2024/20241015-crava... |
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