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Drug Discovery


FAIL EARLY,


FAIL FAST a phenotypic rescue approach


New disease targets frequently emerge in literature, but the thorough target validation required to consider these targets for a drug discovery programme is often lacking.


By DrAnne-Marie Zuurmond,


Dr Geraldine


Servant,Dr Lieke Geerts,Dr Laure Grand Moursel,


Dr Jeroen DeGroot and Dr IanWaddell


I


n pharmacological or genetic perturbation studies using complex biological assays, unde- sired off-target effects cannot be easily distin-


guished from the intended mode of action at the desired target. This is especially evident in cancer drug development where it is important to discrim- inate on-target effects on cell viability from off-tar- get effects resulting in non-specific loss of cellular fitness. Neglecting the possibility of being deceived by off-target effects can have tremendous scientific and financial impact on a drug discovery pro- gramme. Ideally confidence in a preclinical drug target and a modulating compound is boosted in an early stage by more extensive analysis and vali- dation of the actual target-disease or drug-target relationship. Rescue of a relevant phenotype by genetic restoration of a target mutation is a gold standard approach in drug discovery by which tar- get validation can be achieved.


The cost of failure in drug development Drug development is a cost and time-consuming process that can take more than 12 years1 and cost about US$2.6 billion per approved compound2. Such big figures are associated with high risks for the party investing in a drug development pro- gramme for which it is crucial to mitigate the chance of failure and thereby reduce costs involved


34


as much as possible. However, in practice only about 14% of Phase I drugs reach approval. In oncology specifically, drug attrition rates are even higher, with only a meager 3.4% of drugs being licensed3, which represents a huge financial burden on a development programme. Discontinuation of drug development projects during clinical trial is often due to poor efficacy or safety, aspects that may be tackled by more thorough characterisation earlier in the pipeline utilising appropriate biologi- cal models and target validation approaches. CRISPR-Cas9 technology can be used in a simpli- fied phenotype rescue approach, decreasing the sig- nificant pressure on profitability in drug discovery by limiting cost and failure as early as the target validation step.


Common target identification, hit finding and validation approaches Currently the identification of a druggable target (gene, mRNA or protein) associated with a disease phenotype relies mainly on functional genomics and phenotypic screenings. For example, data gen- erated by genome sequencing of individuals, tis- sues and cancers are great resources to identify genomic characteristics, gene mutations or genetic factors associated with disease. Identification of a biological target has also benefited from the


Drug DiscoveryWorld Summer 2019


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