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Small-molecule signal-transduction inhibitors: targeted therapeutic agents for single-gene disorders
  1. D Mark Davies,
  2. Julian R Sampson
  1. Institute of Medical Genetics, Department of Genetics, Haematology and Pathology, School of Medicine, Cardiff University, Cardiff, UK
  1. Correspondence to Dr D Mark Davies, Institute of Medical Genetics, Cardiff University, Cardiff CF14 4XN, UK; daviesdm{at}


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.

  • Molecularly targeted therapy
  • inherited disease
  • getting research into practice
  • clinical genetics

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  • Funding The Trial of Efficacy and Safety of Sirolimus for Tuberous sclerosis and Lymphangioleiomyomatosis (TESSTAL) is funded by the Tuberous Sclerosis Association, the James Tudor Foundation and the Wales Gene Park. Sirolimus is provided free of charge by Wyeth. DMD has also received a contribution to laboratory research costs from Wyeth.

  • Competing interests Both authors participate in research into genetic conditions and could benefit from an increase of funding in this area.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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