Phenocopy – A Strategy to Qualify Chemical Compounds during Hit-to-Lead and/or Lead Optimization

A phenocopy is defined as an environmentally induced phenotype of one individual which is identical to the genotype-determined phenotype of another individual. The phenocopy phenomenon has been translated to the drug discovery process as phenotypes produced by the treatment of biological systems with new chemical entities (NCE) may resemble environmentally induced phenotypic modifications. Various new chemical entities exerting inhibition of the kinase activity of Transforming Growth Factor β Receptor I (TGF-βR1) were qualified by high-throughput RNA expression profiling. This chemical genomics approach resulted in a precise time-dependent insight to the TGF-β biology and allowed furthermore a comprehensive analysis of each NCE's off-target effects. The evaluation of off-target effects by the phenocopy approach allows a more accurate and integrated view on optimized compounds, supplementing classical biological evaluation parameters such as potency and selectivity. It has therefore the potential to become a novel method for ranking compounds during various drug discovery phases.

拟表型（phenocopy）被定义为：由环境因素诱导产生的个体表型，与另一个体由基因型决定的表型完全一致。拟表型现象已被应用于药物研发流程中，因为使用新化学实体（new chemical entities, NCE）处理生物系统所产生的表型，可能与环境诱导的表型修饰相似。多种可抑制转化生长因子β受体I（Transforming Growth Factor β Receptor I, TGF-βR1）激酶活性的新化学实体，通过高通量RNA表达谱分析完成了活性验证。这一化学基因组学方法，为转化生长因子β（TGF-β）的生物学特性提供了精准的时间依赖性认知，同时还可对每一种新化学实体的脱靶效应开展全面分析。通过拟表型方法评估脱靶效应，可使研究人员对优化后的化合物获得更精准且整合性的认知，同时补充了效价、选择性等经典生物学评价指标。因此，该方法有望成为不同药物研发阶段中化合物排序的全新方法。