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
  • 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.

Products