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, Ph.D., 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, Ph.D., 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.
By The Scripps Research Institute
Article can be accessed on: phys.org