Synthetic inhibitors of cancer-promoting proteins

Molecular recognition plays a key role in cellular mechanisms controlled by proteins: indeed, protein-protein and protein-DNA interactions are involved in many processes including signal transduction and DNA transcription. In general, such interactions rely on well-defined networks of non-covalent contacts between amino-acid side-chain or backbone-amide patterns, which determine both the specificity and strength of the binding. The surface area of these networks is usually much larger than that typical for small ligands bound to receptors and enzymes, which makes its targeting with small-size molecules highly improbable. For this reason, more suitable tools have been designed, which mimic natural protein architectures such as a-helices and b-sheets (e.g., peptide foldamers and peptidomimetics) and provide new scaffolds for the building of medium-sized pharmacophores.

 

Our research focuses on the peptide-based development of novel lead structures aiming at the inhibition of protein-protein and protein-DNA interactions involving (proto-)oncoproteins. One of our current targets are the helix-loop-helix (HLH) proteins Id1-4, which are upregulated in several cancer types (e.g., colon, prostate, breast, lung, neuroblastoma) and promote cancer cell proliferation while inhibiting differentiation, support self-renewal of stem cells and cancer-initiating cells, and increase the resistance of cancer cells against chemotherapeutics. We have developed peptide-based compounds that recognize and bind the Id HLH domain, thus blocking the interaction of the Id proteins with their natural protein partners (i.e., bHLH E47/12).

 

The structure-based functional design of potential drug compounds in combination with synthetic methods for their preparation is a broadly used and successful approach to make of cancer-relevant proteins promising druggable targets.

 

Visit Cabrele lab at PLUS

 

Selected publications

 

  • Beisswenger M, Cabrele C. Self-recognition behavior of a helix-loop-helix domain by a fragment scan. Biochimica et biophysica acta 2014;1844:1675-83. IF: 4.5

  • Cabrele C, Martinek TA, Reiser O, Berlicki L. Peptides Containing beta-Amino Acid Patterns: Challenges and Successes in Medicinal Chemistry. Journal of medicinal chemistry 2014;57:9718-39. IF: 5.5

  • Berlicki L, Pilsl L, Weber E, Mandity IM, Cabrele C, Martinek TA, et al. Unique alpha,beta- and alpha,alpha,beta,beta-peptide foldamers based on cis-beta-aminocyclopentanecarboxylic acid. Angewandte Chemie 2012;51:2208-12. IF: 11.3

  • Caporale A, Sturlese M, Gesiot L, Zanta F, Wittelsberger A, Cabrele C. Side chain cyclization based on serine residues: synthesis, structure, and activity of a novel cyclic analogue of the parathyroid hormone fragment 1-11. Journal of medicinal chemistry 2010;53:8072-9. IF: 5.5

Chiara Cabrele, PhD

Professor of Organic Chemistry for Protein Research

Department of Biosciences

University of Salzburg

chiara.cabrele@sbg.ac.at

Innovative peptide inhibitors targeting oncoproteins such as transcription factors

From the target to the lead

The structure of the target (i.e., a proto-oncoprotein) is used to design novel lead structures, which in turn are applied to inhibit the target function.

Cancer Cluster Salzburg at SCRI

3rd Medical Department

Paracelsus Medical University Clinics Salzburg

Müllner Hauptstrasse 48, 5020 Salzburg, Austria

Email: ccs@sbg.ac.at

Cancer Cluster Salzburg at PLUS

Department of Biosciences

University of Salzburg

Hellbrunner Strasse 34, 5020 Salzburg, Austria

Email: ccs@sbg.ac.at