At a concentration of just 1 µM, one experimental compound blocked more than 90% of pancreatic cancer cell migration in lab tests at Florida A&M University. The compound, NSL-YHJ-2-27, belongs to a class called polyisoprenylated cysteinyl amide inhibitors, or PCAIs.
The work was published June 3, 2026 in Volume 17 of Oncotarget. First author Kweku Ofosu-Asante and corresponding author Nazarius S. Lamango, of the university’s College of Pharmacy and Pharmaceutical Sciences in Tallahassee, led the study.
The target
The disease is pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer and among the deadliest. KRAS mutations drive most cases. Drugs such as sotorasib and adagrasib have shown KRAS can be targeted, but they mainly work against one mutation, KRAS G12C. Many pancreatic cancers carry other KRAS mutations, which leaves a gap.
PCAIs were designed to disrupt abnormal KRAS-related signaling and may work more broadly. The team tested 15 of them in pancreatic cancer cells with KRAS mutations. Two stood out, NSL-YHJ-2-45 and NSL-YHJ-2-27, and the researchers then concentrated on the second.
An unexpected mechanism
Treated cells rounded up, lost their stretched-out extensions and became far less mobile. Spreading is a major reason pancreatic cancer kills, which is why the migration result drew attention.
The compound did not shut down the growth pathways downstream of KRAS, as the researchers expected. It drove the MAPK and PI3K/AKT pathways into overdrive. The study suggests that overload becomes harmful to the cancer cells. Treated cells produced more reactive oxygen species and showed signs of apoptosis, a controlled form of cell death. The compound also changed the activity of 88 genes, raising some linked to tumor suppression and lowering others tied to growth, adhesion and invasion.
Results held up in three-dimensional tumor spheroids, which look more like real tumors than flat cultures. The clusters broke apart. At 10 µM, the compound cut invasion by 84% in PANC-1 spheroids and 96% in MIA PaCa-2 spheroids. The two cell lines carry different mutations, KRAS G12D and KRAS G12C.
Early stage
The work was done in cancer cells and spheroids, not in patients. More studies, including animal research, will be needed to learn whether PCAIs are safe, selective and effective in living systems.
Sources
- Experimental compounds trigger cancer cell death in KRAS-driven pancreatic cancer
- New Study Reveals Unexpected Way To Destroy Pancreatic Cancer Cells
