A covalent BTK ternary complex compatible with targeted protein degradation

James Schiemer, Andrew Maxwell, Reto Horst, Shenping Liu, Daniel P. Uccello, Kris Borzilleri, Nisha Rajamohan, Matthew F. Brown and Matthew F. Calabrese ()
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James Schiemer: Pfizer Worldwide Research and Development
Andrew Maxwell: Pfizer Worldwide Research and Development
Reto Horst: Pfizer Worldwide Research and Development
Shenping Liu: Pfizer Worldwide Research and Development
Daniel P. Uccello: Pfizer Worldwide Research and Development
Kris Borzilleri: Pfizer Worldwide Research and Development
Nisha Rajamohan: Pfizer Worldwide Research and Development
Matthew F. Brown: Pfizer Worldwide Research and Development
Matthew F. Calabrese: Pfizer Worldwide Research and Development

Nature Communications, 2023, vol. 14, issue 1, 1-12

Abstract: Abstract Targeted protein degradation using heterobifunctional chimeras holds the potential to expand target space and grow the druggable proteome. Most acutely, this provides an opportunity to target proteins that lack enzymatic activity or have otherwise proven intractable to small molecule inhibition. Limiting this potential, however, is the remaining need to develop a ligand for the target of interest. While a number of challenging proteins have been successfully targeted by covalent ligands, unless this modification affects form or function, it may lack the ability to drive a biological response. Bridging covalent ligand discovery with chimeric degrader design has emerged as a potential mechanism to advance both fields. In this work, we employ a set of biochemical and cellular tools to deconvolute the role of covalent modification in targeted protein degradation using Bruton’s tyrosine kinase. Our results reveal that covalent target modification is fundamentally compatible with the protein degrader mechanism of action.

Date: 2023
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DOI: 10.1038/s41467-023-36738-z

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