Researchers use a new approach to hit an ‘undruggable’ target

Protein degrader shows promise against STAT5, which plays a role in leukemia and other cancers

5:03 AM

Author | Nicole Fawcett

Cancer protein Stat5 cell yellow
Graphical representation of the protein degrader attacking STAT5 Credit: Wang Lab

The protein STAT5 has long been an appealing target against cancer, but after decades of research it was consigned to the “undruggable” category. Now, University of Michigan Rogel Cancer Center researchers have found success with a new approach.

By tapping into a cellular garbage disposal function, researchers found they could eliminate STAT5 from cell cultures and mice, setting the stage for potential development as a cancer treatment.

STAT5 plays a key role in how some blood cancers develop and progress. But efforts to identify a small molecule inhibitor to block STAT5 have been stymied. Previous research efforts have found it challenging to design a drug to bind to STAT5 with a high-affinity, a measure of how well they fit together. Even when a compound was found to bind with the protein, it may not make its way into cell and tissue. It’s also difficult to find a compound that inhibits STAT5 only without affecting any of the other STAT proteins.

Shaomeng Wang, Ph.D., Warner-Lambert/Parke-Davis Professor in Medicine and professor of medicine, pharmacology and medicinal chemistry at the University of Michigan, had another idea.

His lab has been working on a new drug development approach targeting protein degradation. This is a naturally occurring function within cells to get rid of unwanted protein. Think of it as the garbage disposal: When a protein is no longer needed to keep a body healthy, this mechanism removes the unwanted or damaged protein from the cell.

SEE ALSO: Lasting Tumor Regression of Leukemia and Lymphoma in Mouse Models Achieved by U-M Compound

Using this approach, Wang’s lab identified a protein degrader, AK-2292, that targets and removes STAT5. The compound was highly specific to STAT5 with no effect on other STAT proteins. It was effectively taken up by both cell lines and mouse models and was found to stop cell growth in cell lines of human chronic myeloid leukemia (CML) and to induce tumor regression in mouse models of CML. Results are published in Nature Chemical Biology.

The protein degrader works by eliminating STAT5 proteins from tumor cells and tissues, unlike a small molecule inhibitor that would traditionally be designed to bind with the protein and interfere with its function.


“This study shows us STAT5 can be targeted through a protein degradation approach. It’s a new, exciting direction for developing a potential drug molecule targeting STAT5 for the treatment of cancers in which this protein plays a major role.”

Shaomeng Wang, Ph.D.

“We’ve overcome some of the major issues that were barriers for scientists to target STAT5,” Wang said. “People have worked in this field for the last 20 years, and there are no small molecules targeting STAT5 going into clinical development. This study shows us STAT5 can be targeted through a protein degradation approach. It’s a new, exciting direction for developing a potential drug molecule targeting STAT5 for the treatment of cancers in which this protein plays a major role.

“This compound gives us a very solid foundation to do further optimization to identify a compound that we can eventually advance into clinical development,” Wang added.

Wang’s lab has been investigating protein degraders for several years and has a number of degraders in advanced preclinical development studies, which they hope will lead to clinical trials for the treatment of cancer in people.

Additional authors: Atsunori Kaneshige, Longchuan Bai, Mi Wang, Donna McEachern, Jennifer L. Meagher, Renqi Xu, Yu Wang, Wei Jiang, Hoda Metwally, Paul D. Kirchhoff, Lijie Zhao, Hui Jiang, Meilin Wang, Bo Wen, Duxin Sun, Jeanne A. Stuckey

Funding for this work is from Proteovant Therapeutics, Oncopia Therapeutics (acquired by Proteovant), National Cancer Institute grant P30CA046592, U.S. Department of Energy grant DE-AC02-06CH11357, Michigan Economic Development Corporation and Michigan Technology Tri-Corridor grant 085P1000817.

This work was supported by these Rogel Cancer Center Shared Resources: Pharmacokinetics, Proteomics, and Structure and Drug Screening.

Disclosure: The University of Michigan has filed patent applications on inhibitors

and degraders described in this study, which have been licensed to Proteovant Therapeutics. S.W., A.K., L.B. M.W., D.M. and J.S. are co-inventors on one or more of these patent applications and receive royalties from the University of Michigan. The University of Michigan has received a research contract from Proteovant Therapeutics and Oncopia Therapeutics for which S.W. serves as the principal investigator. S.W. is a paid consultant to Proteovant/Roivant and owns equity in Roivant.

Paper cited: “A selective small-molecule STAT5 PROTAC degrader capable of achieving tumor regression in vivo,” Nature Chemical Biology. DOI: 10.1038/s41589-022-01248-4

More Articles About: Cancer: Help, Diagnosis & Treatment Cancer Research Cancer: Cancer Types Leukemia Basic Science and Laboratory Research
Health Lab word mark overlaying blue cells
Health Lab

Explore a variety of healthcare news & stories by visiting the Health Lab home page for more articles.

Media Contact Public Relations

Department of Communication at Michigan Medicine

[email protected]


Stay Informed

Want top health & research news weekly? Sign up for Health Lab’s newsletters today!

Featured News & Stories supar molecule teal blue yellow red
Health Lab
Immune protein suPAR links viral infection as possible cause of kidney disease
Through a series of experiments in non-human primates, mice and humans, a multi-institutional team led by researchers from Michigan Medicine and Rush University found that the immune protein soluble urokinase plasminogen activator receptor, or suPAR, is an important link between viral infections and proteinuria; the elevation of protein in the urine is known to cause glomerulopathy, a common form of kidney disease.
doctor with patient white and black patient ignored
Health Lab
Fixing racial inequities in lupus care
When it comes to lupus care, Black adults are normally left behind despite being one of the highest lupus populations.
Health Lab
Managing scleroderma symptoms through a team approach
Research published in the Arthritis Care and Research Journal from Michigan Medicine found that scleroderma patients made significant strides when working with trained peer health coaches in adhering to wellness routines, leading to resilience and improvements in fatigue, pain and depressive symptoms.
white bowls with allergens in each one
Health Lab
Measuring skin water loss predicts anaphylaxis during food allergy tests
Measuring skin water loss during food allergy tests may help predict anaphylaxis and keep patients safe. The method aims to detect the life threatening reaction before epinephrine injections are necessary
grey needle into cell blue
Health Lab
Mouse model of gender-affirming testosterone treatment and fertility finds decrease in egg yield but not quality
The current IVF recommendation is for transgender patients to stop taking gender-affirming hormones before the procedure, which can be costly and life changing. Now, a team of researchers are diving in further to investigate what the best recommendations should be based on more evidence.
Person tying shoes on floor
Health Lab
Different pain types in multiple sclerosis can cause difficulty staying active
Chronic pain can present in multiple forms for multiple sclerosis patients. Some forms make it harder to stay active than others.