At the recent Keystone Symposium on Modern Phenotypic Drug Discovery: Defining the Path Forward, Bernard Munos (FasterCures, Forbes) made the comment that, “phenotypic screens help us by taking us out of our comfort zones and expose us to evidence that challenges and expands our understanding of biology.” The ability of phenotypic screening to improve our knowledge of disease biology provides a solution for this key bottleneck in drug discovery. Recent late stage clinical failures have reinforced the need to bring biology back into drug discovery. Phenotypic drug discovery is the most direct means for accomplishing this.
What is Phenotypic Drug Discovery
Phenotypic drug discovery relies on screening in intact cells or whole organism models for identification of potential new drugs. This was the historical approach for drug discovery prior to the genomics revolution. In phenotypic drug discovery, selected molecules (identified from chemical libraries, natural products or other bioactive collections) are then tested in animals or humans for desirable therapeutic effects based on the model system used for screening. Model systems, such as DiscoverX’s BioMAP® systems that are highly physiologically relevant are well suited for phenotypic drug discovery.
Renewed Interest in Phenotypic Drug Discovery
Target-based drug discovery (TDD), which has been the primary approach in pharmaceutical drug discovery for the last twenty years, depends on the previous identification and validation of molecular targets prior to high throughput screening. The failure of recent TDD-derived drug candidates in late stage clinical trials have highlighted the limitations of target validation and led to suggestions that perhaps the low hanging fruit have all been picked. This situation has led to a resurgence in interest in phenotypic approaches and the concept that phenotypic drug discovery can play a key role in driving innovation in drug discovery.
Phenotypic drug discovery clinical success stories presented at the Keystone Symposium, in viral diseases (HCV and Ebola), genetic disorders (spinal muscular atrophy and Duchenne muscular dystrophy) and neuropsychiatric disorders showcased the power of phenotypic drug discovery to discover unprecedented targets and pathway mechanisms. With advances in cellular, imaging and ‘omics profiling technologies combined with network and systems biology approaches, the phenotype is no longer the black box that it once was. Expect the renaissance in phenotypic drug discovery to continue.