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Great genetic study but lacking pharmacology

Posted by eperlste on 23 Aug 2012 at 21:58 GMT

Kudos to the authors for showing that drug discovery can start with the humble yeast cell! The awesome power of yeast genetics is a testament to the deep conservation of ancient cellular processes and their circuitous connections to human diseases.

My only complaint is that the paper is light on pharmacology. I wouldn't assume that thiabendazole only targets a single protein or even a single cellular process, and to their credit the authors concede the possibility of more than one mode of action. However, it's been known since the late 70s that thiabendazole binds to tubulin and inhibits its function, though more weakly than its better known structural analogs, nocodazole and benomyl (http://www.ncbi.nlm.nih.g...). In fact, thiabendazole-resistant fungal mutants have been described, which harbor point mutations in tubulin (just Pubmed "thiabendazole AND tubulin"). So there is already strong genetic and biochemical evidence demonstrating that benzimidazole family members can target at least tubulin, and, in the case of thiabendazole, potentially other targets given the high drug concentration required (250µM) to see anti-angiogenic effects. Therefore, it seems as though tubulin should be the starting point of any model of drug action.

The authors did a small structure-activity relationship (SAR) analysis based on commercially available benzimidazole analogs, but I noticed that neither nocodazole nor benomyl were not tested, and I'm curious as to why the tubulin connection wasn't explored further. Also, I'd be curious to know where nocodazole, benomyl and other microtubule poisons cluster in relation to thiabendazole in the original large-scale chemical genomics data set.

Sure, I can believe that RhoA function may be impinged upon by thiabendazole, but by what specific molecular mechanism(s)? I think the challenge going forward for a black-box phenotypic screening approach to drug repurposing is to find a scalable way to resolve polypharmacology using the non-scalable tools of medicinal chemistry.

No competing interests declared.