Application of encoded library technology (ELT) to a protein-protein interaction target: discovery of a potent class of integrin lymphocyte function-associated antigen 1 (LFA-1) antagonists

  • Bioorg Med Chem. 2014 Apr 1;22(7):2353-65. doi: 10.1016/j.bmc.2014.01.050.
Christopher S Kollmann  1 ,  Xiaopeng Bai  1 ,  Ching-Hsuan Tsai  1 ,  Hongfang Yang  1 ,  Kenneth E Lind  1 ,  Steven R Skinner  1 ,  Zhengrong Zhu  1 ,  David I Israel  1 ,  John W Cuozzo  1 ,  Barry A Morgan  1 ,  Koichi Yuki  2 ,  Can Xie  2 ,  Timothy A Springer  2 ,  Motomu Shimaoka  2 ,  Ghotas Evindar  3
Affiliations
  • 1. GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA.
  • 2. Immune Disease Institute, Children's Hospital Boston, Harvard Medical School, Program in Cellular and Molecular Medicine, Department of Biological Chemistry and Molecular Pharmacology, 3 Blackfan Circle, Rm. 3100, Boston, MA 02115, USA.
  • 3. GlaxoSmithKline, Platform Technology & Science, MDR Boston, 830 Winter Street, Waltham, MA 02451, USA. Electronic address: [email protected].
PMID: 24593905 DOI: 10.1016/j.bmc.2014.01.050
Abstract

The inhibition of protein-protein interactions remains a challenge for traditional small molecule drug discovery. Here we describe the use of DNA-encoded library technology for the discovery of small molecules that are potent inhibitors of the interaction between lymphocyte function-associated antigen 1 and its ligand intercellular adhesion molecule 1. A DNA-encoded library with a potential complexity of 4.1 billion compounds was exposed to the I-domain of the target protein and the bound ligands were affinity selected, yielding an enriched small-molecule hit family. Compounds representing this family were synthesized without their DNA encoding moiety and found to inhibit the lymphocyte function-associated antigen 1/intercellular adhesion molecule-1 interaction with submicromolar potency in both ELISA and cell adhesion assays. Re-synthesized compounds conjugated to DNA or a fluorophore were demonstrated to bind to cells expressing the target protein.

Keywords
Affinity-based selections; DNA-encoded libraries; Encoded Library Technology; Intercellular Adhesion Molecule 1; Lymphocyte Function-associated Antigen 1; Protein-Protein Interactions.
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