Selective antagonism of cJun for cancer therapy

Abstract

The activator protein-1 (AP-1) family of transcription factors modulate a diverse range of cellular signalling pathways into outputs which can be oncogenic or anti-oncogenic. The transcription of relevant genes is controlled by the cellular context, and in particular by the dimeric composition of AP-1. Here, we describe the evidence linking cJun in particular to a range of cancers. This includes correlative studies of protein levels in patient tumour samples and mechanistic understanding of the role of cJun in cancer cell models. This develops an understanding of cJun as a focal point of cancer-altered signalling which has the potential for therapeutic antagonism. Significant work has produced a range of small molecules and peptides which have been summarised here and categorised according to the binding surface they target within the cJun-DNA complex. We highlight the importance of selectively targeting a single AP-1 family member to antagonise known oncogenic function and avoid antagonism of anti-oncogenic function.

The Role of AP-1 Transcription Factors in Plasma Cell Biology and Multiple Myeloma Pathophysiology

“…In addition, many efforts have been made to search for peptides which exhibit high affinity for the leucine zipper dimerization domains of c-Jun or c-Fos and to inhibit these bZIP proteins by preventing the formation of functional c-Jun homodimers and c-Jun: c-Fos heterodimers [ 71 , 72 , 73 , 74 , 75 , 76 , 89 ]. Excitingly, an anti-Jun and anti-Fos superzipper has been demonstrated to bind to both the c-Jun and c-Fos leucine zipper peptides [ 77 ].…”

AP-1 family transcription factors: a diverse family of proteins that regulate varied cellular activities in classical hodgkin lymphoma and ALK+ ALCL

“…Even the AP-1 family proteins themselves could become drug targets. Small molecules and peptides that interfere with AP-1 DNA binding or dimer formation are being investigated as therapeutics [ 150 , 151 ] and these could be attractive treatments for cHL and ALK+ ALCL.…”

Combined computational and intracellular peptide library screening: towards a potent and selective Fra1 inhibitor

“…In particular; (i) individual AP-1 members are known to be driven by unique temporal and tissue-specific patterns, impacting upon different target genes. 36 Therefore, a key feature in targeting the correct Fos homologue is not only the ability to impart selectivity, but the ability to deliver the peptide to the particular cell in which the target protein homologue is overexpressed. This has been achieved for example by targeting cancer cells that overexpress specific populations of cell surface receptors that are highly expressed in specific cancers, thereby serving as physiological targets for therapeutic delivery.…”