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April 1, 2013
Chemical Probes Versus Drugs
Nature Chemical Biology has an entire issue on target selection and target validation, and it looks well worth a read. I'll have more to say about some of the articles in it, but I wanted to mention a point that comes up in the introductory comment, "Stay On Target". This is the key point: "Chemical probes and drugs are fundamentally distinct entities".
A drug-company scientist's first reaction might be (as mine was) to think "That's true. The bar is higher for drugs". But the editorial goes on to say that this isn't the case, actually:
For example, multiple authors emphasize that when it comes to in-cell selectivity between on- and off-target activity, chemical probes should be held to a higher standard than drugs, as clinical responses may in fact improve from off-target activity (via polypharmacology), whereas the interpretation of biological responses to chemical probes requires the deconvolution of outcomes associated with on- and off-target activities.
They're right. A drug is defined by its effects in a living creature (I'm tempted to add "Preferably, one that is willing to pay for it"). A chemical probe, on the other hand, is defined by its specificity. It's important not to confuse the two - you can get all excited about how specific your drug candidate is, how exquisitely it hits its target, but (as we have proven over and over in this business) that means nothing if hitting that target isn't clinically meaningful. Being impressed by the specificity of a chemical probe compound, on the other hand, is entirely appropriate - but no one should think that this makes it closer to being a drug.
These concepts came up at the EMBL Chemical Biology meeting I attended last fall, and anyone doing work in the field would do well to keep them in mind. If you don't, you risk producing the worst sorts of compounds. On one end of the spectrum, you have the wonderfully selective compound that has eaten up vast amounts of money in development costs, but does nothing that anyone finds useful. And on the other end of that scale, you have so-called probe compounds that probably hit all sorts of other things, rendering any results in any system past a single purified protein suspect. Stay out of both of those mudpits if you can.
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