The insulin like growth factor (IGF) axis plays a fundamental role in normal growth and development, and when deregulated makes an important contribution to disease. Here, we review the functions mediated by ligand-induced IGF axis activation, and discuss the evidence for the involvement of IGF signaling in the pathogenesis of cancer, endocrine disorders including acromegaly, diabetes and thyroid eye disease, skin diseases such as acne and psoriasis, and the frailty that accompanies aging. We discuss the use of IGF axis inhibitors, focusing on the different approaches that have been taken to develop effective and tolerable ways to block this important signaling pathway. We outline the advantages and disadvantages of each approach, and discuss progress in evaluating these agents, including factors that contributed to the failure of many of these novel therapeutics in early phase cancer trials. Finally, we summarize grounds for cautious optimism for ongoing and future studies of IGF blockade in cancer and non-malignant disorders including thyroid eye disease and aging.

Internalization of ligand-activated type I IGF receptor (IGF1R) is followed by recycling to the plasma membrane, degradation or nuclear translocation. Nuclear IGF1R reportedly associates with clinical response to IGF1R inhibitory drugs, yet its role in the nucleus is poorly characterized. Here, we investigated the significance of nuclear IGF1R in clinical cancers and cell line models. In prostate cancers, IGF1R was predominantly membrane localized in benign glands, while malignant epithelium contained prominent internalized (nuclear/cytoplasmic) IGF1R, and nuclear IGF1R associated significantly with advanced tumor stage. Using ChIP-seq to assess global chromatin occupancy, we identified IGF1R-binding sites at or near transcription start sites of genes including and, most sites coinciding with occupancy by RNA polymerase II (RNAPol2) and histone marks of active enhancers/promoters. IGF1R was inducibly recruited to chromatin, directly binding DNA and interacting with RNAPol2 to upregulate expression of JUN and FAM21, shown to mediate tumor cell survival and IGF-induced migration. IGF1 also enriched RNAPol2 on promoters containing IGF1R-binding sites. These functions were inhibited by IGF1/II-neutralizing antibody xentuzumab (BI 836845), or by blocking receptor internalization. We detected IGF1R on and promoters in fresh prostate cancers that contained abundant nuclear IGF1R, with evidence of correlation between nuclear IGF1R content and JUN expression in malignant prostatic epithelium. Taken together, these data reveal previously unrecognized molecular mechanisms through which IGFs promote tumorigenesis, with implications for therapeutic evaluation of anti-IGF drugs. These findings reveal a noncanonical nuclear role for IGF1R in tumorigenesis, with implications for therapeutic evaluation of IGF inhibitory drugs. .

A surprisingly high number of drug discovery projects begin with a peptide as the initial hit.1-4 These starting molecules typically need significant chemical development as linear peptides have poor pharmacokinetic properties (e.g., oral bioavailability and stability to peptidases). 5,6 Cyclic peptides, however, are far less susceptible to proteolysis 7 and often have increased biological activity because of their conformational rigidity, which decreases entropic loss upon binding. 8,9 In contrast to (and possibly as a result of) their relative underutilization in industry, cyclic peptide libraries have been extensively employed in academia, with multiple approaches developed for their generation. Such work has demonstrated the suitability of the cyclic peptide scaffold for the identification of inhibitors against some of the most challenging targets, including protein-protein interactions (PPIs).10 Macrocyclic peptide scaffolds appear to be optimal for this purpose, and with genetically encoded cyclic peptide libraries in particular, 11,12 there is potential for the straightforward creation of large sequence diversity (e.g., 6.4 × 10 7 members for six randomized amino acids). For synthetic cyclic peptide libraries, there are several approaches for identification of hits, including mass spectrometry, or by sequencing an associated genetic tag (incorporated during library synthesis). 13For the purpose of this review, we have divided cyclic peptide libraries into three main categories: biologic, semisynthetic, and fully synthetic. Some of these libraries are constrained to the canonical peptidogenic amino acids, whereas others are able to include nonpeptidogenic amino acids such as β-or γ-amino acids, D-amino acids, or nonnatural amino acids. 14-16The majority of biologically produced cyclic peptide libraries are formed using phage/phagemid display 8,17 or by splitintein cyclisation of peptides and proteins (SICLOPPS). 11,18,19 The latter uses a selectively randomized library of splitinteins for the production of genetically encoded, backbone cyclized peptide libraries. Semisynthetic libraries are able to incorporate nonpeptidogenic amino acids while retaining ribosomal synthesis and an associated genetic tag. The most frequently used method for semisynthetic library production is mRNA display 7,20 ; novel variants thereof include random nonstandard peptide integrated discovery (RaPID) 14 or protein synthesis using recombinant elements (PURE).15 Both methods use promiscuous enzymes to expand the amino acid library encoded into peptides by reprogramming codons. 16Another semisynthetic technique has been used for the creation of macrocyclic organic-peptide hybrids (MOrPHs) 21,22 and bicyclic organo-peptide hybrids (BOrPHs), 23 which produce geometrically constrained peptide libraries. Fully AbstractThe identification of initial hits is a crucial stage in the drug discovery process. Although many projects adopt high-throughput screening of small-molecule libraries at this stage, there is significant potential for s...

Cyclic peptides are an important class of molecules that are increasingly viewed as an ideal scaffold for inhibition of protein-protein interactions (PPI). Here we detail an approach that enables the intracellular synthesis of cyclic peptide libraries of around 10 members. The method utilizes split intein mediated circular ligation of peptides and proteins (SICLOPPS), taking advantage of split intein splicing to cyclize a library of peptide sequences. SICLOPPS allows the ring size, set residues and number of random residues within a library to be predetermined by the user. SICLOPPS libraries have been combined with a variety of cell-based screens to identify cyclic peptide inhibitors of a variety of enzymes and protein-protein interactions.

We report an inhibitor of the homodimeric protein-protein interaction of the BCL6 oncoprotein, identified from a genetically encoded SICLOPPS library of 3.2 million cyclic hexapeptides in combination with a bacterial reverse two-hybrid system. This cyclic peptide is shown to bind the BTB domain of BCL6, disrupts its homodimerization, and subsequent binding of the SMRT2 corepressor peptide.