Late-stage functionalization with strain-release warheads enables tunable covalent inhibition
Abstract
Covalent inhibition continues to gain momentum as a strategy for selective protein modulation in both therapeutic and chemical biology contexts. Covalent reactive groups (CRGs) typically engage nucleophilic residues such as cysteine, resulting in targeted protein inactivation. However, common electrophiles such as acrylamides often suffer from nonselective reactivity, leading to off-target effects and toxicity. To overcome these limitations, we developed a modular sulfur(IV) reagent platform for the mild, late-stage installation of sulfonyl- and sulfonimidoyl-bicyclobutane motifs with complete cysteine selectivity. This methodology enables access to diverse sulfur(VI) CRGs with tunable strain-release reactivity. Incorporation into US Food and Drug Administration–approved covalent inhibitors demonstrated effective bioisosteric replacement of acrylamides and the potential of strain-release CRGs for selective protein targeting. Preclinical studies in mice have validated this approach, highlighting its promise for next-generation covalent drug design.
Article Details
Journal Info
Science
American Association for the Advancement of Science
Authors (18)
Zachary P. Shultz
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Ansar Lee-Sam
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Yun-Pu Chang
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Luxin Sun
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Dylan Grassie
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Alessio Gabellini
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Kyle Pedretty
Department of Chemistry, University of South Florida, Tampa, FL, USA.
Thomas Scattolin
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Victoria Izumi
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Bin Fang
Proteomics and Metabolomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Samer Sansil
Cancer Pharmacokinetics and Pharmacodynamics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Ramu Kakumanu
Cancer Pharmacokinetics and Pharmacodynamics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Lukasz Wojtas
Department of Chemistry, University of South Florida, Tampa, FL, USA.
John Koomen
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Ernst Schönbrunn
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Andrii Monastyrskyi
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Derek Duckett
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
Justin M. Lopchuk
Drug Discovery Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.