Research at the Centre for Protein Degradation

The Centre for Protein Degradation was developed out of years of degraders research by scientists who explored targeted protein degradation (TPD) as a therapeutic modality. Our extensive structural biology and screening capabilities are utilised to design and identify promising leads for developing novel PROTAC and MGD platforms. 

The Centre for Protein Degradation has two main objectives:

1) Apply TPD for cancer patient benefit, and
2) Discover and develop new TPD approaches.

To address these objectives, the CPD is focusing on three main research themes: 

1. PROTACs

PROteolysis Targeting Chimeras (PROTACs) are heterobifunctional molecules rationally designed to bring the desired target protein in close proximity to an E3 ubiquitin ligase, and consequently induce its ubiquitination and proteasomal degradation. A typical PROTAC consists of three distinct structural motifs, with one binding to the protein of interest, another binding to an E3 ligase complex (a warhead), and a linker tethering them together.

We have put in place and are constantly developing key enabling tools such as an extensive library of linker-warhead intermediates to enable rapid PROTAC synthesis and SAR exploration, and E3-ligase engagement assays to study ternary complex formation.

The Centre's portfolio handles several ongoing PROTAC projects; if you are interested in collaborating with us, please contact us. 

2. Molecular glue degraders

Molecular Glue Degraders (MGDs) bind to E3 ubiquitin ligase altering its substrate specificity, which results in the recruitment, ubiquitination, and subsequent proteasomal degradation of proteins not normally targeted by the E3 ligase, termed neosubstrates.

The ICR has been at the forefront of this field since 2016, with our research leading to the development of the spin-out company, Monte Rosa Therapeutics, who are currently conducting a Phase I/II clinical trial of MRT-2359, a potent and selective GSPT1-directed molecular glue degrader.

A second generation cereblon (CRBN) directing library has been developed, and is continuously being diversified and expanded using the state-of-the-art computational and structural biology design methods. The library is screened in phenotypic and target-defined biochemical and cell-based assays to discover novel MGDs and neosubstrates.

Animation reproducing the working hypothesis with a known CRBN molecular glue degrader (Lenalidomide). DDB1 is shown as blue/violet surface in complex with CRBN (pink ribbons), which rearranges from the open to the closed conformation. Lenalidomide binds to the closed conformation and triggers the binding of the neosubstrate, CK1α (in green). A final close-up view focuses on its glycine degron.

3. Enabling novel E3 ubiquitin ligases

While there around 600 E3 ligases in the human genome, only a few of them are currently being utilised in TPD drug discovery, with most attention placed on Von–Hippel Lindau (VHL) and cereblon (CRBN). Enabling alternative E3 ligases for TPD is an important aspect of our research efforts since it would expand the range of proteins that can be targeted and the range of cells or tissues in which the degrader would be effective, thereby shifting the sensitivity or resistance profile. The CPD employs advanced computational methods to identify druggable E3 ligases that are cancer drivers and/or differentially expressed in tumours.