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Small-Molecule Screening for Genetic Diseases
Annual Review of Genomics and Human Genetics ( IF 7.7 ) Pub Date : 2018-08-31 00:00:00 , DOI: 10.1146/annurev-genom-083117-021452
Sarine Markossian 1 , Kenny K. Ang 1 , Christopher G. Wilson 1 , Michelle R. Arkin 1
Affiliation  

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.

中文翻译:


遗传疾病的小分子筛查

已经确定了许多疾病的遗传决定因素,包括单基因疾病和癌症。然而,大多数情况下,靶向治疗仍然遥遥无期。小分子的高通量筛选(HTS),包括高含量分析(HCA),已成为发现分子工具和新疗法的重要技术。HTS可以基于已知疾病目标的调节(称为反向化学遗传学)或疾病相关机制或表型的调节(正向化学遗传学)。基于靶标的突出成功包括用于治疗转甲状腺素蛋白淀粉样蛋白的运甲状腺素蛋白调节剂和用于治疗慢性粒细胞白血病的BCR-ABL激酶抑制剂Gleevec。表型筛选成功包括囊性纤维化跨膜电导调节剂,脊柱肌肉萎缩症的校正剂和癌症的组蛋白脱乙酰基酶抑制剂。合成致死性筛查是一种有望将表型与靶标融合的有前途的方法,其中针对特定的遗传背景对化学治疗剂进行筛查。在本文中,我们将介绍HTS技术,并重点介绍其对发现单基因疾病和癌症的药物和探针的贡献。

更新日期:2018-08-31
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