Activator protein 1 (AP-1) is a transcription factor that regulates gene expression in response to a variety of stimuli. Specifically, AP-1 controls many cellular processes, including differentiation, proliferation, and apoptosis. Meanwhile, AP-1 transcription factors are assembled by dimerization of bZIP domains in fos and Jun subunits. Jun protein can form a stable dimer and bind to AP-1 DNA recognition element, also known as TRE. This is because they mediate the transcriptional induction of TPA, a tumor promoter of phorbol ester. Nonetheless, AP-1 activity is usually regulated by post-translational modification, DNA binding dimer composition, and interaction with various binding partners. Besides, the AP-1 transcription factor is relevant to the growth of breast cancer cells through a variety of mechanisms, including the regulation of cyclin D1, E2F, and their target genes.

Transcription factors NF-κB and AP-1 are induced by oxidative stress and a variety of stimulating responses including pro-inflammatory cytokines such as TNF-α. Moreover, Redox plays an important role in regulating the transcription of AP-1 and NF-κB. The transcriptional activity of AP-1 is redox-sensitive due to the increased expression of AP-1 induced by reactive oxygen species (such as H2O2). Here, we will introduce a selective AP-1 transcription inhibitor, PNRI-299.

PNRI-299 is a Selective AP-1 Transcription Inhibitor.

How does brd3308 work on the target? Let’s study it together. In the beginning, PNRI-299 is a selective AP-1 transcription inhibitor with an IC₅₀ of 20 uM. Importantly, PNRI-299 is a selective APE/Ref-1 inhibitor. Particularly, PNRI-299 has no effect on NF-κB transcription (up to 200 uM) or thioredoxin (up to 200 uM). PNRI-299 significantly reduces airway eosinophil infiltration, mucus hypersecretion, edema, and IL-4 levels in a mouse asthma model.

In the second place, PNRI-299 specifically reacts with Ref-1 to inhibit AP-1 transcription and overexpress its molecular target. Importantly, Ref-1 attenuated the inhibitory effect of PNRI-299 on AP-1 transcription. Particularly, PNRI-299 interacts with the redox nucleophile cys-65, which helps to explain the structure-activity relationship (SAR).

Last but not the least, PNRI-299 significantly reduced the inflow of eosinophils, monocytes, and macrophages into the lung interstitium and bronchoalveolar lavage fluid. Obviously, PNRI-299 significantly reduced airway mucus and edema. Additionally, PNRI-299 reduced the pathophysiological response observed in this allergic asthma mouse model.

All in all, PNRI-299 is a selective AP-1 transcription inhibitor.

References:

Nguyen C, et al. Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):1169-73