2. Academic Validation
  3. Cereblon covalent modulation through structure-based design of histidine targeting chemical probes

Cereblon covalent modulation through structure-based design of histidine targeting chemical probes

  • RSC Chem Biol. 2022 Jul 8;3(9):1105-1110. doi: 10.1039/d2cb00078d.
Justin T Cruite 1 2,  Geoffrey P Dann 1 2,  Jianwei Che 1 2,  Katherine A Donovan 2 3,  Silas Ferrao 1,  Scott B Ficarro 4 5,  Eric S Fischer 1 2 3,  Nathanael S Gray 6,  Fidel Huerta 1,  Nikki R Kong 1 2,  Hu Liu 1 2,  Jarrod A Marto 4 5,  Rebecca J Metivier 3,  Radosław P Nowak 1 2,  Breanna L Zerfas 1 2,  Lyn H Jones 1 2
Affiliations

Affiliations

  • 1 Center for Protein Degradation, Dana-Farber Cancer Institute Boston MA USA lyn_jones@dfci.harvard.edu.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School Boston MA USA.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute Boston MA USA.
  • 4 Department of Cancer Biology, Department of Oncologic Pathology, and Blais Proteomics Center, Dana-Farber Cancer Institute Boston MA USA.
  • 5 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School Boston MA 02115 USA.
  • 6 Department of Chemical and Systems Biology, ChEM-H, Stanford Cancer Institute, School of Medicine, Stanford University Stanford CA USA.
PMID: 36128501 DOI: 10.1039/d2cb00078d
Abstract

Electrophilic biocompatible warheads, particularly cysteine-reactive acrylamides, have enabled the development of covalent inhibitor drugs and chemical biology probes, but cysteine is rarely present in protein binding sites. Therefore, expansion of the list of targetable amino acid residues is required to augment the synthetic bology toolkit of site-selective protein modifications. This work describes the first rational targeting of a specific histidine residue in a protein binding site using sulfonyl exchange chemistry. Structure-based drug design was used to incorporate sulfonyl fluoride and triazole reactive groups into the isoindolinone thalidomide congener EM12 to yield potent covalent inhibitors of the Cereblon E3 ubiquitin Ligase complex through engagement of His353. Conversely, the fluorosulfate derivative EM12-FS labels His353, but degrades a novel neosubstrate, the protein N-terminal glutamine amidohydrolase NTAQ1, which is involved in the N-end rule pathway and DNA damage response. Targeted protein degradation using Cereblon ligands has become an important new drug discovery modality and the chemical probes and covalent labeling strategy described here will broadly impact this exciting area of therapeutic research.

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