The promise of phenotypic screening resides in its track record of novel biology and first-in-class therapies. However, challenges stemming from major differences between target-based and phenotypic screening do exist. These challenges prompted us to rethink the critical stage of hit triage and validation on the road to clinical candidates and novel drug targets. Whereas this process is usually straightforward for target screening hits, phenotypic screening hits act through a variety of mostly unknown mechanisms within a large and poorly understood biological space. Our analysis suggests successful hit triage and validation is enabled by three types of biological knowledge—known mechanisms, disease biology, and safety—while structure-based hit triage may be counterproductive.

表型筛选的希望在于其对新生物学和一流疗法的记录。但是，确实存在基于靶点筛查和表型筛查之间主要差异的挑战。这些挑战促使我们重新思考命中分类和验证在临床候选药物和新型药物靶标道路上的关键阶段。尽管此过程通常对于靶标筛选命中是简单的，但表型筛选命中是通过在一个广为人知且不为人所知的生物空间中的各种几乎未知的机制起作用的。我们的分析表明，成功的命中分类和验证可以通过三种类型的生物学知识（已知的机制，疾病生物学和安全性）来实现，而基于结构的命中分类可能会适得其反。