Development of AXL-degrading proteolysis targeting chimeras (PROTACs) for the treatment of pancreatic cancer
Pancreatic cancer is the 3rd most common cause of cancer related deaths, with only a 10.8% 5-year survival rate post-diagnosis. Current standard treatments use combinations of chemotherapies. However, these therapies have inadvertent complications such as severe toxicity and the development of resistance. In this project we tested the activity of 12 novel proteolysis targeting chimeras (PROTACs) that were designed to degrade the AXL protein which is known to play an important role in the growth, invasion, immune response, and drug resistance of multiple cancers including pancreatic cancer. We measured the survival rate of treated MIA PaCa-2 and PANC-1 pancreatic cancer cells using Sulforhodamine B (SRB) staining, and performed Western blotting to determine AXL levels in treated and untreated cells. Two compounds (XW-3-ELA4 and XW-3-ELA5) had the greatest effect on MIA PaCa-2 cell survival, and another two compounds (TAM-977 and TAM-6C) had the greatest effect on PANC-1 cell survival. Of these, the XW-3-ELA4 and XW-3-ELA5 compounds were the most active in degrading AXL protein. These resutls provide guidance for the further optimization of the compounds and aid the future development of targeted pancreatic cancer therapies.