Goal: To identify and optimize targeted protein degraders that selectively eliminate the cancer-driving DNAJ-PKAc fusion protein in fibrolamellar carcinoma while sparing normal proteins
Principal Investigator: Fleur Ferguson, PhD
Grant length: Six months
Study overview: Dr. Fleur Ferguson (UC San Diego), in collaboration with Dr. Nabeel El-Bardeesy (Massachusetts General Hospital), is exploring whether targeted protein degradation can be used to treat fibrolamellar carcinoma (FLC). Unlike traditional drugs that simply block a protein’s activity, targeted degraders eliminate disease-causing proteins from the cell. The team has developed a lead degrader, JEK-01-186, that selectively targets overactive forms of PKACA. This selectivity is critical because normal PKACA plays essential roles in healthy tissues, including the the heart, and previous PKACA inhibitors have been limited by toxicity. A goal is to determine if JEK-01-186 reduces DNAJ-PKAc levels in FLC cell models and inhibits tumor cell growth, while having minimal effects on healthy cells.
The proposed work will:
- Develop high-throughput cellular assays to measure degradation of DNAJ-PKAc in FLC models.
- Determine how cellular signaling pathways affect degrader activity and selectivity.
- Screen and validate a library of PKACA-targeted degraders to identify the most potent and selective candidates.
If successful, the project could identify promising drug candidates and establish a robust platform for future therapeutic development. More broadly, it could determine if selective degradation of the fusion protein is a feasible therapeutic strategy for FLC.