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.

  • http://twitter.com/eperlste Ethan Perlstein

    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.

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    • http://twitter.com/eperlste Ethan Perlstein

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

  • http://twitter.com/sargoshoe Sara G

    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.