Evolutionarily Repurposed Networks Reveal the Well-Known Antifungal Drug Thiabendazole to Be a Novel Vascular Disrupting Agent

August 24, 2012

Analysis of a genetic module repurposed between yeast and vertebrates reveals that a common antifungal medication is also a potent vascular disrupting agent.

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4 Comments. Leave new

Ethan Perlstein
08.24.12 9:51 am

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.

Reply
Ethan Perlstein
08.24.12 12:36 pm

No worries! FYI, there is a link “Read on Mendeley” on the side panel under Mendeley Metrics.

Reply

I think this is a cool result but I wonder how many other examples the lab will be able to find that are as mindblowing as this given their coarse definition of pathway conservation. If even one protein in a pathway is missing from yeast to human, the conservation of the drug response could be lost (e.g. it only took the absence of one domain to break the UPR in protozoa http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0019118 ).

Once the genetic interactions can really scale up to multi-cellular organisms and be identified in specific tissues, I think this approach can be extremely powerful, as you can identify complete conserved pathways rather than just single proteins.

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