Selective chemical probe + disease relevant biology = target validation ??

Target validation is a critical part of the drug discovery process – after all the best drug against the wrong target will still lead to failure in the clinic. Although well used, the phrase ‘target validation’ doesn’t necessarily mean the same thing to all and the acceptable level of validation or data package to support a target varies considerably from group to group and company to company. A clear disease linkage to human genetics is considered by many to be the strongest validation for a clinically unproven target. However this is still complex to achieve, particularly for diseases likely to be polygenic in their aetiology. Even monogenetic diseases where we know the identity of the gene and have clarity on how that affects protein and cellular function have been challenging – it’s taken over 20 years to get from the identification of the cystic fibrosis gene (CFTR) to the introduction of the first drug to ‘correct’ the genetic defect (Kalydeco in 2013).

The use of chemical probes to enable us to functionalise the genome and identify new drug targets is an approach that continues to gain credibility, particularly when combined with human cell based test systems (the merits or otherwise of animal models is perhaps best left for a future blog). However if the data generated using a chemical probe is to be correctly interpreted then the chemical probe needs to have a well defined and selective pharmacological mechanism of action ie. the quality of the conclusion will be directly related to the quality of the probe. In a recent article in Nature Chemical Biology (11, 536-541) Cheryl Arrowsmith, along with other academic and industry colleagues discuss the appropriate (…and inappropriate) use of chemical probes – they also provide some thoughtful advice and guidelines in addition to advocating the open sharing of best practices.

From Arrowsmith et al (2015) The promise and peril of chemical probes. Nature Chemical Biology 11, 536-541

From Arrowsmith et al (2015) The promise and peril of chemical probes. Nature Chemical Biology 11, 536-541

A key part of the Sussex Drug Discovery Centre’s role is to develop novel chemical probes with the aim of facilitating target validation. If you have a target that you think a chemical probe would ‘enable’ then we’d really like to hear from you!

Blog written by Martin Gosling