A graphic depicting the function of a PROTAC. The kinase inhibitor component of the PROTAC (light blue oval) binds the kinase target (dark blue), and the E3 ubiquitin ligase inhibitor component (yellow) binds the E3 ubiquitin ligase (yellow oval) allowing the E2 enzyme (teal) to transfer ubiquitin (Ub, teal circle) onto the kinase target to promote its degradation.
A recent study suggests that a group of novel therapeutic molecules called PROTACs (proteolysis targeting chimeras) could be helpful in overcoming resistance to a class of anti-cancer drugs called PIM kinase inhibitors, which are used to treat a wide range of cancers. The results were published online November 16, 2023, in Cell Chemical Biology.
A kinase is a type of protein that cells use to perform specific functions. “PIM kinases get activated in tumor microenvironments to help cancer thrive,” explains John Brognard, Ph.D., Senior Investigator in the Laboratory of Cell and Developmental Signaling. “Basically, the proteins promote survival, proliferation and growth of those tumors in low-oxygen environments.”
To improve outcomes for cancer patients, scientists developed drugs that inhibit PIM kinase activity. However, some patients develop resistance to these drugs, causing their disease to progress despite treatment.
Brognard’s team was studying this phenomenon in mice, noting that simply the presence of these kinases was enough to promote tumor growth, even when the activity of PIM kinases was inhibited with drugs. This prompted them to team up with Rolf E. Swenson, Ph.D., Director of the Chemistry and Synthesis Center at the NIH National Heart, Lung, and Blood Institute.
Swenson specializes in engineering sophisticated therapeutic molecules called proteolysis targeting chimeras (PROTACs). These molecules are composed of three parts: a binder that attaches to a kinase, a linker and another binder that targets an E3 Ubiquitin ligase, leading to the degradation of the kinase and essentially eliminating the kinase altogether.
In total, Swenson’s lab created several different PROTACs targeting PIM kinases, which Brognard then tested in a series of experiments with prostate cancer cells in petri dishes. The results show that breaking down PIM kinases using these PROTACs was a more potent strategy to limiting tumor growth than simply inhibiting their activity using PIM kinase inhibitors.
“By generating PROTACs to promote degradation of the target, we are able to overcome that mechanism of resistance,” explains Brognard.
This was especially true when the researchers applied a chemotherapy drug in combination with the PROTACs. When the chemotherapy drug docetaxel was applied alone to the cell culture, about 12% of the cancer cells died. When docetaxel was combined with one of the more effective PROTACs in this study, cell death increased to 40%.
PIM kinases have been found to be overexpressed not just in prostate cancer, but in breast, colon, endometrial, gastric and pancreatic cancers, as well as hematological malignancies, suggesting that these novel PROTACs could be widely applicable to many patients. However, Brognard notes that the PROTACs in this recent study are first-generation, and more research would be needed to modify them for testing in a clinical trial in humans.