title: Increasing the range of drug targets: interacting peptides provide leads for the development of oncoprotein inhibitors.
abstract: Two limiting aspects are mainly responsible for the sluggish development of new cancer drugs. They concern the chemical properties of potential drug molecules and the structural prerequisites for drug targets. The chemical properties which are being considered desirable for potential drugs are rather restrictive and mainly dictated by the rules of oral availability. Drug target structures are mostly defined as molecules which comprise binding pockets for low molecular weight compounds. These low molecular weight compounds then serve as leads for the derivation of analogs which recognize the same site and which can function as competitive or irreversibly binding inhibitors. The extension of the range of drug targets and the design of suitable lead compounds will be one of the most challenging tasks for drug developers in the future. Such auxiliary drug target structures can be found in the complex networks of interacting proteins which constitute the intracellular signal transduction cascades. The transient assembly of high molecular weight complexes, based on the specific interactions of particular domains, and usually regulated by secondary modifications, propagates extracellular signals through the cytoplasm and into the nucleus. Aberrations in the formation of protein complexes, or in the regulation of their disassembly, often trigger pathological conditions. The interference with interactions of proteins or the interactions of proteins with DNA offer new opportunities for drug discovery and development. Protein complexes which are indispensable for the growth and survival of cancer cells, proteins to which these cells are "addicted," appear most suited for such an approach. Stat3 and Survivin have been used as model proteins. Specific peptide ligands able to recognize and suppress the functions of crucial interaction surfaces of these proteins have been derived and shown to be able to induce cancer cell death. However, further technology development is required to turn such ligands into useful drugs. The technology comprises three steps: (1) the identification of a peptide ligand which specifically interacts with a crucial functional domain of a target protein, (2) the induction of a desired cellular phenotype upon intracellular interaction of the peptide ligand with its target structure and (3) the replacement of the peptide ligand with a functionally equivalent low molecular weight, drug like compound and its optimization through medicinal chemistry.
authors: Georg Speyer Haus Institute for Biomedical Research, Frankfurt am Main, Germany. groner@em.uni-frankfurt.de
authors: Bernd
authors: B
authors: Groner
authors: Axel
authors: A
authors: Weber
authors: Laura
authors: L
authors: Mack
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D055808:Drug Discovery; D005293:Ferritins / Q000737:chemistry / Q000235:genetics; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D009369:Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000378:metabolism; D015513:Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010088:Oxidoreductases; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D011485:Protein Binding; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D008024:Ligands; D015513:Oncogene Proteins; D010455:Peptides; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000077022:Survivin; D005293:Ferritins; C454461:FTH1 protein, human; D010088:Oxidoreductases