Targeted protein degradation (TPD), induced by enforcing proximity in cells between a target protein and an enzyme called E3 ubiquitin ligase using small molecules has become an important drug discovery approach for targeting previously undruggable disease-causing proteins.
Human cells contain more than 600 E3 ligases but so far only around 10 E3 ligases have been utilised for TPD. Expanding the pool of E3 ligases that can target the degradation of disease-causing proteins is an important next step in TPD drug discovery space.
By using the Affinity-directed PROtein Missile (AdPROM) system that was developed in the Sapkota lab, a joint team from the Sapkota lab and GSK screened over 30 different E3 ligases for their ability to target the degradation of 4 disease-relevant target proteins, namely K-RAS, STK33, b-catenin and FoxP3. From this screen, the team identified several new E3 ligases, including the CUL2-diGly receptor KLHDC2, emerged as effective degraders, suggesting that these E3 ligases are good candidates for the development of small molecule degraders, such as PROteolysis TArgeting Chimeras (PROTACs). Excitingly, the team developed a KLHDC2-recruiting peptide-based PROTAC and provided proof-of-concept for TPD through endogenous KLHDC2.
This study published in Cell Chemical Biology was led by Sapkota lab postdoctoral fellows Sascha Roth and Nur Kocaturk, a PhD student Bill Carton, Matthew Watt and Thomas J. Macartney from the MRC PPU, and the GSK team lead by Markus Queisser - Preethi Sathyamurthi, a joint Dundee/GSK PhD student, Kwok-Ho Chan, Albert Isidro-Llobet and Agnieszka Konopacka.
The paper, published in Cell Chemical Biology on August 16th 2023, can be found here
(Sascha Roth is now a senior scientist at Astra Zeneca. Nur Kocaturk is currently a postdoctoral fellow at the Centre for Targeted Protein Degradation in University of Dundee. Following completion of his PhD, Bill Carton is now a postdoctoral scientist at Amphista Therapeutics.)