My research interests focus on developing and utilising Targeted Protein Degradation (TPD) approaches to study cancer biology and discover novel cancer treatments. Towards this goal, my group research efforts centre around three main themes: PROTAC, Molecular Glue Degraders, and novel E3 ligases.

PROteolysis Targeting Chimeras (PROTACs)

My earlier research in PROTAC development led to the realisation that immunomodulatory drug (IMiD) based PROTACs rapidly hydrolyse even under mild conditions such as cell culture media, which significantly affects their cellular potency (PMID: 34614283). To address this liability, we designed novel CRBN-directing warheads with improved overall properties compared to IMiDs, namely Phenyl Glutarimide (PG) and Phenyl Dihydrouracil (PD), and demonstrated their versatility and superiority over IMiDs for the design and development of PROTACs (PMID: 34614283; 36793425; 35300081; PMID: 36001679; 36793425; 34110416). We have access to a large library of linker-E3 warhead intermediates and a wide range of biochemical and cell-based assays that enable us to rapidly develop potent and selective PROTACs suitable for in vivo proof-of-concept studies.

Molecular Glue Degraders (MGDs)

Whereas the PROTAC approach to target protein degradation greatly benefits from rational design, the discovery of small-molecule degraders relies mostly on phenotypic screening. Building on the experience from earlier programs and success in discovering potent, selective, and orally bioavailable MGDs (PMID: 34042448; 37172201; 38228616), we are now rapidly expanding our second-generation library, using the accumulated SAR, cheminformatics, and structural biology data. To identify novel neosubstrates and MGDs, the library is screened against a range of cancer cell lines developed by our collaborators at the ICR and Royal Marsden Hospital.

Enabling novel E3 ubiquitin ligases

While the human genome encodes over 600 E3 ubiquitin ligases, TPD is currently limited to the few for which ligands have been reported, mostly CRBN and VHL. Identifying druggable E3 ligases that are oncogenic drivers, or/and differentially expressed in tumours, will not only broaden the spectrum of tractable target oncoproteins but will also introduce additional levers for improving the efficacy, selectivity, and safety of protein degraders. We apply bioinformatics approaches using assembled and harmonised genomics, transcriptomics, and proteomics data to define the landscape of E3 dependencies and expression patterns in cancer and select E3 ligases for this program (PMID: 33004795).