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Frag rocks

You gotta walk before you can run. Actually, you usually have to crawl before you walk. For small molecule drug discovery in the early days, we were talking more about not moving at all from serendipitous discoveries, with maybe a little floundering around in the hope of discovering something new. Basically, when you can potentially synthesize almost any organic small molecule and you have little idea how biological systems will treat that little guy, there’s not much to light the way.

A big advance, as we’ve noted before, was the development of metrics, like Lipinski’s rule of 5. But those rules for how to crawl through the space quickly became harnesses, as that chemical space became seen to be somewhat fully mined, especially with respect to structure-based drug discovery. Notably, the list of “undruggable” targets grew larger with each genomic analysis.

So how to explore new chemical space for drug discovery? Well, Lipinski’s rule has upper and lower size limits to it. Phenotypic discovery proved that the upper limit was something of a straw man. And one of the more interesting technological developments concerned pushing against the lower boundary: some researchers argued that those smaller fragments, while incapable of being drugs, could still be bait in the drug fishing process. To wit, the small fragments with weak drug activity against a desirable target could still potentially be visualized crystallographically and utilized as scaffolds to make something entirely new and effective, especially by combining two nearby scaffolds.

Well, as appealing as this idea was, screening for micromolar potency fragments and then crystallizing them seemed, well, low-yield. Still, the fans of this approach persisted and achieved one of the great advances in modern biomedicine in the BRAF inhibitor.

The story is quite entertaining. A single point mutation in BRAF, which is part of the canonical growth signalling pathway, is the most frequently mutated gene in melanoma cancer, so a drug was needed to target that mutated form over the wild-type form. The folks at the company formerly known as Plexxion took the fragment approach and were able to bootstrap a few fragments into a novel chemical entity with a high specificity for the mutated BRAF. Lo and behold, the drug had first-in-class type activity against melanoma. Sometimes, you have to look at the boundaries of the space to advance . . .

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