Unexpected discoveries in the targeted protein degradation of squalene synthase and DCAF15

Protein degradation is a universal process performed by human cells to recycle unused proteins and to adapt to an ever-changing environment. Targeted protein degradation (TPD) is a new approach for the treatment of human diseases, where these normal degradation processes are hijacked. Instead of simply blocking a protein’s function, heterobifunctional or monovalent small molecules are used to redirect a specific protein to the cellular protein degradation machinery. If so-called PROteolysis Targeting Chimeras (PROTACs) or molecular glues are developed successfully, they can eliminate all functions of a protein, including catalytic and scaffolding roles. Thereby, TPD can help to unlock yet untreatable diseases and open up new strategies to uncover new biology.
In two separate projects within this thesis, the aim was to apply TPD principles to develop degraders of squalene synthase (SQS) and DDB1 Cul4 Associated Factor 15 (DCAF15), two unrelated proteins. SQS is a metabolic enzyme, catalyzing a key step in cholesterol biosynthesis. I wanted to investigate if chemical degradation of SQS could prevent cholesterol biosynthesis and thereby lower overall cholesterol content in human cancer cells. I identified a small molecule degrader of SQS, which was able to lower amounts of the storage form of cholesterol in cells, cholesterol esters. At the same time, I identified so far unknown stabilizers of SQS, which shielded the protein from its natural turnover. Overall, the work shows that SQS protein levels can be manipulated with diverse chemical structures, which can guide future compound development.
DCAF15 is the substrate receptor (SR) component of the Cullin 4 Ring Ligase (CRL4) complex, which is one part of natural cellular protein degradation processes. Recent discoveries strongly implicate DCAF15 in protein aggregation, which is a hallmark of neurodegenerative diseases. By developing the first small molecule degraders of DCAF15, I aimed to test the therapeutic potential of chemically eliminating DCAF15 for the treatment of e.g. Alzheimer’s or Parkinson’s disease. After identifying early leads, I am currently in the process of biologically evaluating our compounds.