Fail Early, Fail Fast - A Phenotypic Rescue Approach

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conceptual image of A1 receptors with G-proteins in cell membrane

Drug Discovery World

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.

In pharmacological or genetic perturbation studies using complex biological assays, undesired off-target effects cannot be easily distinguished from the intended mode of action at the desired target. This is especially evident in cancer drug development where it is important to discriminate on-target effects on cell viability from off-target 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 programme. Ideally confidence in a preclinical drug target and a modulating compound is boosted in an early stage by more extensive analysis and validation 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 target validation can be achieved.

Posted with kind permission from Drug Discovery World Vol. 20 Iss.3 Summer 2019.

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