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Small-Molecule Screening for Genetic Diseases

Authors
  • Markossian, Sarine
  • Ang, Kenny K.
  • Wilson, Christopher G.
  • Arkin, Michelle R.
Type
Published Article
Journal
Annual Review of Genomics and Human Genetics
Publisher
Annual Reviews
Publication Date
Aug 31, 2018
Volume
19
Pages
263–288
Identifiers
DOI: 10.1146/annurev-genom-083117-021452
Source
Annual Reviews
Keywords
License
Yellow

Abstract

The genetic determinants of many diseases, including monogenic diseases and cancers, have been identified; nevertheless, targeted therapy remains elusive for most. High-throughput screening (HTS) of small molecules, including high-content analysis (HCA), has been an important technology for the discovery of molecular tools and new therapeutics. HTS can be based on modulation of a known disease target (called reverse chemical genetics) or modulation of a disease-associated mechanism or phenotype (forward chemical genetics). Prominent target-based successes include modulators of transthyretin, used to treat transthyretin amyloidoses, and the BCR-ABL kinase inhibitor Gleevec, used to treat chronic myelogenous leukemia. Phenotypic screening successes include modulators of cystic fibrosis transmembrane conductance regulator, splicing correctors for spinal muscular atrophy, and histone deacetylase inhibitors for cancer. Synthetic lethal screening, in which chemotherapeutics are screened for efficacy against specific genetic backgrounds, is a promising approach that merges phenotype and target. In this article, we introduce HTS technology and highlight its contributions to the discovery of drugs and probes for monogenic diseases and cancer.

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