target validation
Target validation is the work of proving that hitting a particular protein will actually help against a disease, before a team invests years and large sums chasing it. It is like checking that a suspect is really the culprit before building an entire case around them. The aim is to replace a hopeful guess with solid evidence.
Researchers validate a target by perturbing it in many ways and watching what happens to the disease. They may delete or silence the gene, use a tool molecule to block the protein, or examine human genetics linking the target to the condition. Convergent results from several independent methods give confidence that modulating this target produces the desired effect, not a coincidence.
Strong target validation reduces the risk that a drug will fail late, after it has already proven it can bind and behave well, simply because the target was the wrong one. The honest caveat is that no preclinical model perfectly mirrors human disease, so even a well-validated target can disappoint in the clinic, which is why human genetic evidence is prized.
Human genetic evidence that people with naturally low PCSK9 activity have low cholesterol and few heart attacks helped validate PCSK9 as a target before drugs against it were proven.
Human genetics is among the most trusted forms of target validation.
A chemical probe, a highly selective tool molecule, is often used to test whether modulating a target produces a useful effect during validation.