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

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

Na Ye  1 , Ye Ding, Christopher Wild, Qiang Shen, Jia Zhou
Affiliations

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

Na Ye et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
Number of papers published between 1990 and 2013 according to recent PubMed search using “AP-1”.
Figure 2
Figure 2
Structures of AP-1 (c-Fos/c-Jun, PDB code 1Fos).
Figure 3
Figure 3
AP-1 associated signaling pathways.
Figure 4
Figure 4
Chemical structures of 1 and its representative analogues 2–20.
Figure 5
Figure 5
Chemical structures of 21–28.
Figure 6
Figure 6
Chemical structures of analogues based on modifications of hit 29.
Figure 7
Figure 7
Chemical structures of analogues based on modifications of hit 39.
Figure 8
Figure 8
Discovery of 51, a selective AP-1 inhibitor in phase II human clinical trial.
Figure 9
Figure 9
Chemical structures of K1115A, curcumin, and their analogues. Abbreviations in the peptides are the following: A, Ala; K, Lys; C, Cys; N, Asp; R, Arg.
Figure 10
Figure 10
Momordin I and its analogues.
Figure 11
Figure 11
Isosteviol and its analogues.
Figure 12
Figure 12
Chemical structures of quassinoids with AP-1 inhibitory effects.
Figure 13
Figure 13
Natural products 93–96 and other AP-1 inhibitors 97 and 98.
See this image and copyright information in PMC

References

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    1. Uchihashi S.; Fukumoto H.; Onoda M.; Hayakawa H.; Ikushiro S.; Sakaki T. Metabolism of the c-Fos/activator protein-1 inhibitor T-5224 by multiple human UDP-glucuronosyltransferase isoforms. Drug Metab. Dispos. 2011, 39, 803–813. - PubMed

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