Small molecule inhibitors targeting activator protein 1 (AP-1)

J Med Chem. 2014 Aug 28;57(16):6930-48. doi: 10.1021/jm5004733. Epub 2014 May 27.

Abstract

Activator protein 1 (AP-1) is a pivotal transcription factor that regulates a wide range of cellular processes including proliferation, apoptosis, differentiation, survival, cell migration, and transformation. Accumulating evidence supports that AP-1 plays an important role in several severe disorders including cancer, fibrosis, and organ injury, as well as inflammatory disorders such as asthma, psoriasis, and rheumatoid arthritis. AP-1 has emerged as an actively pursued drug discovery target over the past decade. Excitingly, a selective AP-1 inhibitor T-5224 (51) has been investigated in phase II human clinical trials. Nevertheless, no effective AP-1 inhibitors have yet been approved for clinical use. Despite significant advances achieved in understanding AP-1 biology and function, as well as the identification of small molecules modulating AP-1 associated signaling pathways, medicinal chemistry efforts remain an urgent need to yield selective and efficacious AP-1 inhibitors as a viable therapeutic strategy for human diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arthritis, Rheumatoid / drug therapy
  • Arthritis, Rheumatoid / metabolism
  • Benzophenones / pharmacology
  • Biological Products / chemistry
  • Biological Products / pharmacology
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Isoxazoles / pharmacology
  • Maleimides / chemistry
  • Maleimides / pharmacology
  • Molecular Targeted Therapy / methods
  • Neoplasms / drug therapy
  • Neoplasms / metabolism
  • Organic Chemicals / chemistry
  • Organic Chemicals / pharmacology
  • Quinazolines / chemistry
  • Quinazolines / pharmacology
  • Signal Transduction / drug effects
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Transcription Factor AP-1 / chemistry*
  • Transcription Factor AP-1 / metabolism*
  • Transcription Factors / chemistry
  • Transcription Factors / metabolism

Substances

  • 3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzophenones
  • Biological Products
  • Isoxazoles
  • Maleimides
  • Organic Chemicals
  • Quinazolines
  • SP 100030
  • SPC-839
  • Small Molecule Libraries
  • Transcription Factor AP-1
  • Transcription Factors