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Auld ligands syne

The massive inefficiency of target-based high-throughput screening eventually led to major pivots in the pharmaceutical industry. The biggest was to jump the drug-like small molecule ship altogether and develop biologic drugs (drugs that are proteins/antibodies). This pivot has been wildly successful, with most of the highest revenue drugs these days being biologics. The result emphasized that successful pivots from the tradition needed to focus on critical challenges to target-based discovery, namely the reasons why those drugs failed. In the case of biologics, the focus was on target specificity in biology: Antibodies are WAY more specific than drug-like small molecules.

However, that ship was a veritable aircraft carrier. For the massive numbers of participants, it was not easy to turn around. Hence, the next biggest pivot, and our theme of the month, was to stay with drug-like small molecules but focus on phenotypes, rather than targets. The failure/challenge here was to admit that biology was far more complex than a single target, so focus on the biology (but . . . shhh, don’t tell anyone . . . work back to the target!).

Well, some die-hards didn’t even stop there. You can’t teach an old dog new tricks. As for medicinal chemists? Well . . . woof. Fortunately, some creative academics long ago had already been poking around on the fringes of target-based, drug-like small molecules and came up with an interesting idea that focused on on an even more specific reason for drug failure: The millstone of potency and residence time–drug-like small molecules need to bind VERY tightly to their targets and stay bound for a long time. That’s hard to engineer, even for the best Rhodesian Ridgeback . . . er . . . medicinal chemist. So these folks took advantage of something new that had just been discovered in biology: the protein degradation machinery that cleans up molecules in all cells. By using chemical ligands to non-covalently cross link the protein degradation machine to protein targets, the chemical ligands did not have to bind very well or for very long; they just needed to act long enough to bring the pair together and POOF the target protein was permanently gone. They called the new approach Protacs, and boy has it caught on now, with several startups already in clinical trials. Sometimes referred to as “chemical handles” and or “targeted protein degradors,” these compounds are redefining the rules of medicinal and computational chemistry. Looks like we at Genecentrix have our work cut out for us again!

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