Small molecules and their roles in effective pre-clinical target validation

Clegg, Michael and Tomkinson, Nicholas C. O. and Prinjah, Rab K. and Humphreys, Philip G. (2017) Small molecules and their roles in effective pre-clinical target validation. Future Medicinal Chemistry. ISSN 1756-8919 (In Press)

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As demonstrated in multiple historical analyses, there are two main causes of clinical attrition; firstly drugs are not efficacious, and secondly they cause unacceptable toxicity, both of which can be the result of poor pre-clinical target validation. Target validation, one of the early stages of a drug discovery program, is the process of (in) validating a drug target to ensure it is significant to the intended disease, and unlikely to drive undesired toxicity. Target validation is vital in preventing late stage failures in the clinic and, if done effectively, can save pharmaceutical companies a great deal of time and money. As such, target validation is treated extremely seriously, as demonstrated by the formation of public - private partnerships, such as Open Targets, aimed to provide evidence of biological validity and the possible likelihood of pharmacological intervention. Central to the variety of molecular tools available for use in target validation are high quality small molecules called chemical probes.