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Screening Approaches for the Identification of Covalent Peptide Inhibitors

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Abstract: Stratified medicine is poised to fundamentally alter cancer therapy but is currently limited to just 10% of patients. This is due to a lack of inhibitors for most cancer proteins, which are often deemed undruggable as they lack binding pockets that can be targeted with small molecules. Undruggable proteins possess reactive nucleophilic residues that can be interrogated by targeted covalent inhibitors (TCIs). Most TCIs target cysteines, but many proteins lack cysteine residues. Electrophiles have been reported for nine other amino acids, but few unbiased screening methods exist to identify TCIs from diverse pools of candidate molecules. Consequently, the full potential of TCIs for targeting undruggable proteins is yet to be realised. Our research aims to address this by using combinatorial chemistry and phage display to develop ultra-large libraries of covalent peptides for screening. Specifically, we develop libraries of targeted covalent macrocycles (TCMs) by cyclising billions of phage-displayed linear peptides with reactive linkers possessing latent electrophilic moieties. TCMs have the combined properties of a macrocyclic peptide (high affinity and specificity) and a covalent inhibitor (durable target engagement) and are particularly effective at engaging undruggable protein targets. 1. Chen, S., Lovell, S., Lee, S., Fellner, M., Mace, P. D., & Bogyo, M. (2021). Identification of highly selective covalent inhibitors by phage display. Nature Biotechnology, 39 (4), 490–498. 2. Lovell, S., et al., (2021). A Suite of Activity-Based Probes To Dissect the KLK Activome in Drug-Resistant Prostate Cancer. Journal of the American Chemical Society, 143 (23), 8911–8924.

This talk is part of the Seminars on Quantitative Biology @ CRUK Cambridge Institute series.

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