New “protein-degrading” compounds show promise against aggressive pancreatic and gastrointestinal cancers (Figure 1).
Figure 1: Graphical abstract.
Pancreatic cancer remains one of the deadliest malignancies, notoriously resistant to chemotherapy and prone to spreading within the abdominal cavity. Now, researchers have developed a new way to attack the disease by destroying, rather than merely blocking, a key cancer-promoting enzyme.
In a recent paper, scientists have created a “molecular crowbar” that pries apart and degrades Pin1, an enzyme overexpressed in many cancers. The findings could pave the way for a new class of protein-degrading drugs that directly dismantle cancer’s molecular machinery.
Pin1 acts as a molecular switchboard, regulating both oncogenes and tumour suppressors within cancer cells and their surrounding microenvironment. It plays a particularly dangerous role in pancreatic and gastrointestinal cancers, where it drives tumour growth and helps shield cancer cells from treatment by fortifying the fibrous, protective tissue around tumours.
To counter this, the team designed small molecules that bind to Pin1 and destabilize its structure, triggering its breakdown inside the cell. These degraders not only affect cancer cells but also disrupt tumour-supporting fibroblasts and macrophages, helping to dismantle the tumour’s protective stroma.
By enhancing the plasma stability of their Pin1 degraders, the researchers were able to test their effects on patient-derived fibroblasts and in mouse models of pancreatic cancer peritoneal metastases, an advanced, hard-to-treat stage of disease where cancer spreads across the abdominal lining.
Unlike traditional inhibitors that simply block enzyme activity, Pin1 degraders remove the protein altogether, a growing strategy in modern drug design known as targeted protein degradation.
A powerful new “molecular crowbar” that breaks down a key cancer-driving enzyme could offer a fresh path forward for treating some of the most lethal cancers, turning the concept of blocking cancer proteins into one of removing them altogether.
Journal article: Alboreggia., G., et al, 2025. Pre-clinical evaluation of a potent and effective Pin1 degrading agent in Pancreatic Cancer. Molecular Therapy Oncology.
Summary by Stefan Botha
