Jointly targeting IGF-1R and IR in cancer

Jointly targeting IGF-1R and IR in cancer

Partnering opportunity in cancer: 

Jointly targeting IGF-1R and IR in cancer

 

Team

Professor Mike Lawrence, Associate Professor Chris Burns, Associate Professor Guillaume Lessene

Background

Insulin-like growth factor receptor (IGF-1R) is a trans-membrane tyrosine kinase receptor, which plays a key role in mitogenesis, transformation and protection from apoptosis.

Over-expression is associated with a wide variety of cancers including breast, colorectal and prostate. Activation of IGF-1R pathways appears to be an escape mechanism for therapies targeted at the epidermal growth factor receptor (EGFR).

Recent clinical trial outcomes lead to the conclusion that successful targeting of IGF-1R requires co-targeting with the insulin receptor (IR). This explains the failure of anti-IGF-1R monoclonal antibodies and tyrosine kinase inhibitors in multiple Phase III trials.

The technology

Our researchers have discovered a novel, common and druggable site on the extracellular component of IGF-1R. This finding offers a completely new strategy in cancer therapy - co-targeting of IGF-1R and IR using small molecules.

The primary IGF/insulin binding site lies on the first leucine-rich repeat domain (L1) of the receptor. The C-terminal segment of the receptor α-chain (αCT) is required for ligand binding, and our scientists have shown that this segment has a helical conformation and interacts with the L1 surface. This tandem arrangement then forms the intact ligand-binding site.

Our researchers have shown this native peptide segment interacts only weakly with the L1 domain and can be displaced from it by certain non-native peptides that bind the L1 domain surface with higher affinity. The nature of the interaction of these peptides with the L1 domain surface indicates that they, in turn, can be readily mimicked, for example by small molecule helical peptide mimetics.

We have commenced a drug discovery project aimed at identifying potent small molecule inhibitors of αCT binding. We have screened our internal 114,000 compound library and subsequent structure guided medicinal chemistry optimization of hit compounds has generated drug-like lead compounds with sub-mM activity and clear structure activity relationships. Our ongoing medicinal chemistry program seeks to capitalise on this progress to further optimise these lead compounds.

Applications

While the primary focus is on targeting IGF-1R and IR in cancer, small molecules based on this technology may have application in other disease states, including diabetes and Alzheimer’s disease.

Intellectual property

We hold two national phase patents relating to the structure of the insulin receptor ectodomain (WO2007147213 and WO2010121288).

The patent family describes the coordinates of the insulin receptor ectodomain and protects the use of these in the design of small molecules that target the αCT site. Compound structures have not been publicly disclosed. An opportunity exists to generate novel composition of matter intellectual property.

Opportunity for partnership

We seek a partner to invest in the development of novel small molecule compounds that target the αCT site. All relevant technologies are in place to undertake this development:

  • high-throughput screening
  • structural biology
  • hit-to-lead technologies
  • helical mimetic framework medicinal chemistry
  • cell based assays of IGF-1R and IR phosphorylation
  • tumour cell proliferation

Key publications

  • Menting JG. et al. Structural Congruency of Ligand Binding to the Insulin and Insulin/Type 1 Insulin-like Growth Factor Hybrid Receptors. Structure. 2015 Jul 7;23(7):1271-82 PMID: 26027733
  • Menting JG. et al. How insulin engages its primary binding site on the insulin receptor. Nature. 2013 Jan 10;493(7431):241-5 PMID: 23302862
  • Smith BJ. et al. Structural resolution of a tandem hormone-binding element in the insulin receptor and its implications for design of peptide agonists. Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6771-6 PMID: 20348418
  • Menting JG. et al. A thermodynamic study of ligand binding to the first three domains of the human insulin receptor: relationship between the receptor alpha-chain C-terminal peptide and the site 1 insulin mimetic peptides. Biochemistry. 2009 Jun 16;48(23):5492-500 PMID: 19459609

Contact

Dr David Segal, Technology Development Associate

Phone: +61 3 9345 2418 Email: segal@wehi.edu.au

 

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