A new drug destroys one of cancer’s most common driver proteins instead of simply blocking it, demonstrating the potential of a new class of medicines known as targeted protein degraders.
Some of the deadliest cancers, including many pancreatic, colorectal and lung cancers, share a common genetic alteration in a protein called KRAS. A single change in this protein can permanently switch on signals that tell cells to keep growing and dividing. Because KRAS mutations drive millions of cancers worldwide, they have become one of the most intensively studied targets in cancer research.
Most drugs developed against KRAS work by blocking the mutant protein and preventing it from sending growth signals. These treatments have produced important advances, but the protein itself remains inside the cell and can regain activity or develop resistance through additional mutations.
A new strategy takes a different approach. Rather than simply blocking mutant KRAS, a drug called Setidegrasib causes the cancer cell to destroy it. The drug belongs to a new class of medicines known as targeted protein degraders, which harness the cell’s own recycling machinery to eliminate disease-causing proteins instead of temporarily shutting them down. The study provides one of the strongest demonstrations yet that targeted protein degradation may offer a new way to treat cancers driven by mutant KRAS.
A Different Kind of Drug
Traditional targeted drugs work much like putting a cap over a keyhole. They bind to a protein and prevent it from carrying out its normal function. When the drug leaves, the protein can work again because it remains inside the cell.
Targeted protein degraders use the cell’s own recycling machinery instead. Rather than simply attaching to a protein, they mark it for destruction. Cells constantly recycle damaged or unnecessary proteins by attaching small molecules called ubiquitin to them. These molecular tags direct the proteins to the cell’s recycling center, where they are broken down into their building blocks and removed.
Targeted degraders redirect this natural process toward disease-causing proteins. The degrader itself is not toxic. Instead, it acts brings the harmful protein into contact with the recycling machinery so it can be tagged with ubiquitin. Once the protein has been destroyed, the degrader is released and can repeat the process with additional protein molecules. Instead of blocking a protein’s activity for a limited time, the drug removes the protein altogether.
How Setidegrasib Works
Setidegrasib, a targeted protein degrader, was engineered to target mutant KRAS, a protein that helps regulate normal cell growth. When KRAS acquires certain mutations, it becomes permanently switched on, driving uncontrolled cell division in many lung, colorectal and pancreatic cancers.
The drug recognizes KRAS proteins carrying specific mutations, including several of the most common cancer-causing KRAS variants. The drug binds to a pocket that forms only when KRAS carries one of these mutations. This allows the drug to distinguish cancer cells from healthy cells, directing degradation toward the mutant protein while largely sparing normal tissues.
After binding mutant KRAS, Setidegrasib recruits an enzyme that attaches ubiquitin molecules to the protein, marking it for destruction. The cell’s recycling machinery then breaks KRAS apart, removing it completely rather than simply preventing it from signaling.
Unlike conventional inhibitors, which must remain attached to continuously suppress their target, a single Setidegrasib molecule can trigger degradation of multiple KRAS proteins before being reused.
Why Degradation May Be Better Than Inhibition
Destroying a protein changes how long treatment continues to work. Conventional inhibitors lose their effect once they detach from the protein. The protein remains inside the cell and can quickly resume its activity. In contrast, degradation removes the protein entirely. The cell must first manufacture a replacement before signaling can begin again.
Degradation may also reduce opportunities for drug resistance. Cancer cells often acquire mutations that weaken drug binding while allowing the protein to keep functioning. Eliminating the protein altogether may overcome some forms of resistance that limit conventional inhibitors.
The approach could also expand the range of proteins that medicines can target. Many disease-causing proteins lack a suitable site where traditional drugs can bind tightly enough to block their activity. A degrader does not always need to shut the protein down directly. It only needs to bind well enough to recruit the cell’s recycling machinery and trigger destruction.
Beyond KRAS
Setidegrasib represents more than another KRAS drug. It demonstrates how targeted protein degradation could reshape drug development. Because the same strategy can be adapted to many different targets, it may become a general approach for eliminating harmful proteins that have previously been considered beyond the reach of medicine.
Much work remains before targeted degraders become widely available. Clinical studies will determine which diseases respond best and which proteins can be safely eliminated. Even so, the field is moving rapidly.
For decades, drug development has focused on finding ways to block disease-causing proteins. Targeted protein degradation suggests that the next generation of medicines may instead remove them altogether.