2. Academic Validation
  3. Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2

  • Nat Commun. 2023 Oct 10;14(1):6345. doi: 10.1038/s41467-023-41894-3.
Sarath Ramachandran # 1,  Nikolai Makukhin # 1 2,  Kevin Haubrich 1,  Manjula Nagala 1,  Beth Forrester 1,  Dylan M Lynch 1,  Ryan Casement 1,  Andrea Testa 1 2,  Elvira Bruno 1,  Rosaria Gitto 3,  Alessio Ciulli 4
Affiliations

Affiliations

  • 1 Centre for Targeted Protein Degradation, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee, DD1 5JJ, United Kingdom.
  • 2 Amphista Therapeutics Ltd, Cory Building, Granta Park, Great Abington, Cambridge, CB21 6GQ, United Kingdom.
  • 3 Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, Viale Stagno D'Alcontres 31, Pole Papardo, 98166, Messina, Italy.
  • 4 Centre for Targeted Protein Degradation, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, 1 James Lindsay Place, Dundee, DD1 5JJ, United Kingdom. a.ciulli@dundee.ac.uk.
  • # Contributed equally.
PMID: 37816714 DOI: 10.1038/s41467-023-41894-3
Abstract

The Src homology 2 (SH2) domain recognizes phosphotyrosine (pY) post translational modifications in partner proteins to trigger downstream signaling. Drug discovery efforts targeting the SH2 domains have long been stymied by the poor drug-like properties of phosphate and its mimetics. Here, we use structure-based design to target the SH2 domain of the E3 Ligase suppressor of cytokine signaling 2 (SOCS2). Starting from the highly ligand-efficient pY amino acid, a fragment growing approach reveals covalent modification of Cys111 in a co-crystal structure, which we leverage to rationally design a cysteine-directed electrophilic covalent inhibitor MN551. We report the prodrug MN714 containing a pivaloyloxymethyl (POM) protecting group and evidence its cell permeability and capping group unmasking using cellular target engagement and in-cell 19F NMR spectroscopy. Covalent engagement at Cys111 competitively blocks recruitment of cellular SOCS2 protein to its native substrate. The qualified inhibitors of SOCS2 could find attractive applications as chemical probes to understand the biology of SOCS2 and its CRL5 complex, and as E3 Ligase handles in proteolysis targeting chimera (PROTACs) to induce targeted protein degradation.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-156395
    98.05%, 半胱氨酸导向的亲电共价抑制剂
  • HY-156373
    POM抑制剂
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