2. Academic Validation
  3. Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction

Structural Basis of Small-Molecule Aggregate Induced Inhibition of a Protein-Protein Interaction

  • J Med Chem. 2017 Apr 27;60(8):3511-3517. doi: 10.1021/acs.jmedchem.6b01836.
Jonathan M Blevitt 1,  Michael D Hack 2,  Krystal L Herman 1,  Paul F Jackson 1,  Paul J Krawczuk 3,  Alec D Lebsack 4,  Annie X Liu 5,  Taraneh Mirzadegan 2,  Marina I Nelen 6,  Aaron N Patrick 5,  Stefan Steinbacher 7,  Marcos E Milla 1,  Kevin J Lumb 5
Affiliations

Affiliations

  • 1 Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
  • 2 Lead Discovery, Discovery Sciences, Janssen R&D LLC , La Jolla, California 92121, United States.
  • 3 Immunology, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
  • 4 Immunology, Janssen R&D LLC , La Jolla, California 92121, United States.
  • 5 Emerging Science & Innovation, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
  • 6 Lead Discovery, Discovery Sciences, Janssen R&D LLC , Spring House, Pennsylvania 19477, United States.
  • 7 Proteros Biostructures , 82152 Martinsried, Germany.
PMID: 28300404 DOI: 10.1021/acs.jmedchem.6b01836
Abstract

A prevalent observation in high-throughput screening and drug discovery programs is the inhibition of protein function by small-molecule compound aggregation. Here, we present the X-ray structural description of aggregation-based inhibition of a protein-protein interaction involving tumor necrosis factor α (TNFα). An ordered conglomerate of an aggregating small-molecule inhibitor (JNJ525) induces a quaternary structure switch of TNFα that inhibits the protein-protein interaction between TNFα and TNFα receptors. SPD-304 may employ a similar mechanism of inhibition.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-124339
    TNFα Inhibitor