PDE6D/KRAS inhibitor development for cancer treatment (inhibitPDE-RASv2)

The project at a glance

Start date:

01 May 2021
Duration in months:

27
Funding:

FNR
Principal Investigator(s):

Prof. Dr. Daniel Abankwa

About

KRAS is the most frequently mutated oncogene and a potent driver of tumorigenesis. It is highly mutated in common and deadly cancers such as of the lung, colon and pancreas. After 40 years of intensive research, only in 2021 was the first direct inhibitor against a specific KRAS mutant (KRAS-G12C) approved. In this project we have developed pre-clinical inhibitors against a surrogate target of KRAS, called PDE6D. PDE6D facilitates the movement of the normally membrane bound KRAS inside cells. If binding of PDE6D to KRAS is blocked, KRAS does not reach its normal membrane destinations and remains inactive. Several experimental inhibitors against PDE6D were developed, however, they suffered from poor solubility and off-target effects. Within this project we generated a series of improved inhibitors that were tested for their activity to hit the correct target PDE6D in cells, selectively reduce cancer cell viability and tumor growth. Our best inhibitor, Deltaflexin3, binds with low nanomolar affinity to PDE6D and is very well soluble, a prerequisite for currently ongoing in vivo experiments. Most recent data from our research suggest that this inhibitor could be combined with another approved drug to suppress cancer stem cell properties, which drive metastatic spread of many cancers. We are currently looking for collaboration/ licensing partners in biotech/pharma for our patented invention.