Kendall Nettles, Ph.D., employs computer models to reveal how hormones, the body’s chemical messengers, and their receptors work together. The goal? To tackle real-world medical problems, including cancer drug resistance.
Exploring the Language of Hormones
Hormones play critical roles in diseases like breast and prostate cancer. Hormones are chemical messengers. They
work by linking up with a receptor, setting off a series of changes in cells. Sometimes cancer exploits these signaling systems to evade treatment, grow and spread. Kendall Nettles and his team use artificial intelligence and the University of Florida’s supercomputer, HiPerGator, to understand structural biology, biochemistry and medicinal chemistry interactions to invent new ways to prevent disease progression.
Nettles has an ideal background for this work. He earned his doctorate with the researcher who first discovered the estrogen receptor
gene, Geoffrey Greene, Ph.D., at the University of Chicago. Nettles’ research on steroid hormones and inflammation continued at Scripps Florida, now The Wertheim UF Scripps Institute. His lab’s current focus is to improve treatment of hormone dependent cancers by developing new AI methods.
The Sophisticated Estrogen Receptor
For many years, researchers believed estrogen receptors acted in pairs that simply turned “on” or “off” when bound by estrogen or anti-hormone drugs. Nettles’ group discovered that estrogen receptors were much more sophisticated. Different hormones and drugs can induce tiny shifts in the receptor’s shape that can create major changes to the effects inside cells. These tiny structural differences explain why some drugs and environmental estrogens can cause unexpected or tissue-specific effects.
Nettles’ work has also revealed that drug-receptor communication is not one-way. The receptor itself can influence a drug ‘s activity. And when two molecules bind to a receptor pair, they can produce unique, combined effects that differ from what each would cause individually. These discoveries have challenged the traditional “lock and key” view of drug action. Nettles’ group has applied these insights to develop dual-mechanism estrogen receptor inhibitors, potential medicines able to both block the receptor and distort its structure in For many years, researchers believed estrogen receptors acted in pairs that simply turned “on” or “off” when bound by estrogen or anti-hormone drugs.
Nettles’ group discovered that estrogen receptors were much more sophisticated. Different hormones and drugs can induce tiny shifts in the receptor’s shape that can create major changes to the effects inside cells. These tiny structural differences explain why some drugs and environmental estrogens can cause unexpected or tissue-specific effects. Nettles’ work has also revealed that drug-receptor
communication is not one-way. The receptor itself can influence a drug ‘s activity. And when two molecules bind to a receptor pair, they can produce unique, combined effects that differ from what each would cause individually.
These discoveries have challenged the traditional “lock and key” view of drug action. Nettles’ group has applied these insights to develop dual-mechanism estrogen receptor inhibitors, potential medicines able to both block the receptor and distort its structure in a desired way. This innovative approach shows promise against breast cancers that have become resistant to standard hormone therapies.
Tackling Prostate Cancer
Nettles’ work also extends to prostate cancer, where resistance to androgen receptor-targeted treatments remains a major challenge. Some tumors adapt by relying upon cortisol, a stress hormone that regulates both the immune system and inflammation through its receptor. Nettles and his collaborators are studying these mechanisms to design compounds that can block these escape routes and restore treatment effectiveness.
Through this understanding, his lab aims to help create next-generation therapies that prevent tumors from evading control. They also hope to create precision steroid medications for treating adverse effects of immunotherapies, and many other anti-inflammatory applications.
Designing Safer Steroid Therapies
Beyond cancer, Nettles’ research has implications for millions of patients who rely on glucocorticoid steroid drugs to treat inflammation and autoimmune disease. These drugs are highly effective but can cause serious side effects, including muscle wasting and bone loss, obesity and diabetes. Nettles’ team is developing tissue-selective medications that preserve steroids’ anti-inflammatory benefits while reducing harm to other organs.
A Foundation for Future Therapies
Nettles’ lab continues to explore how small structural changes in hormone receptors translate into large differences in cell behavior. By linking molecular structure to biological response, his research provides a foundation for designing safer and more effective therapies for breast and prostate cancers and inflammatory diseases.