title: Interfering with protein-protein interactions: potential for cancer therapy.
abstract: Genotype-specific cancer therapy promises to engender the era of personalised medicines in which rapid identification of tumour specific gene mutations coupled to rapid methods for efficacious drug identification will be applied. Aberrant signal transduction via protein-protein interactions is generally difficult to target with small molecules. However, macromolecules (macrodrugs) can be developed that interfere with protein-protein interactions by binding with high affinity and specificity to contact surfaces. Inhibitors of mutant RAS and its effector protein interactions affect cancer by attenuating aberrant RAS-dependent signal transduction and would be effective against mutant RAS in dividing cells of overt tumours and in putative cancer stem cells when they move into cell-cycle. Results with an antibody fragment blocking effector binding to RAS, illustrates that this is sufficient to prevent cancer. While macrodrugs have inherent problems of bio-distribution and delivery to target cells in patients, their efficacy suggests that efforts to achieve the goal of clinical use should be pursued.
authors.affiliation: Leeds Institute of Molecular Medicine, Wellcome Trust Brenner Building, St. James's University Hospital, Leeds, United Kingdom.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Tanaka
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
mesh_terms: D015195:Drug Design; D006801:Humans; D046911:Macromolecular Substances / Q000378:metabolism* / Q000627:therapeutic use; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000628:therapy*; D015398:Signal Transduction / Q000502:physiology*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D046911:Macromolecular Substances; D018631:ras Proteins