title: Small-molecule signal-transduction inhibitors: targeted therapeutic agents for single-gene disorders.
abstract: Mutations affecting over 2000 of the 20 000 or so genes in the human genome have been linked so far to specific inherited diseases, most of which are rare and have been poorly understood. Many of the genes involved encode components of intracellular signalling pathways that regulate processes such as the growth, proliferation, differentiation and survival or programmed death of cells during development and the maintenance of tissues and organs. Mutations that change the function of genes encoding signalling proteins thereby cause disorders ranging from birth defects to cancer. For Mendelian disorders, the essentially causal relationship between mutation and disease may present direct opportunities to therapeutically manipulate intracellular signalling. Here, we review recent examples of the use of small-molecule drugs to target components of signalling networks in single-gene disorders. We also consider the limitations of these "molecularly targeted" approaches and the difficulties in their clinical development as therapies for rare genetic diseases.
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK. daviesdm@cardiff.ac.uk
authors.forename: D Mark
authors.initials: DM
authors.lastname: Davies
authors.forename: Julian R
authors.initials: JR
authors.lastname: Sampson
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D030342:Genetic Diseases, Inborn / Q000188:drug therapy*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D008954:Models, Biological; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics; D004364:Pharmaceutical Preparations / Q000008:administration & dosage* / Q000032:analysis / Q000302:isolation & purification; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D054852:Small Molecule Libraries / Q000032:analysis
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries