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Jan
16

What can we predict about BIA 10-2474

**UPDATE As of 21st Jan 2016 please note the actual structure of BIA 10-2474 changed to this.

 

In the past few days we learnt about the clinical trial that went terribly wrong in France leaving several volunteers in a very serious condition. In involves a compound from a company called Bial and the compound is believed to be BIA 10-2474. Chris Southan has done much to describe the difficulty associating the structure and molecule ID.

Of course it begs the question why was this potential risk not picked up earlier. We must assume the company provided all the preclinical data in animals and human cells before reaching this point. Is there anything else we can do? I thought about just trying to predict potential activities for the compound – assuming the one being described mainly online is the one responsible. I have run the possible molecule through several Bayesian models in the mobile app called PolyPharma. This app has selected targets of interest for drug repurposing and also some well known off-targets / ADME-Tox targets. The models are a subset of over 2000 which were developed by Alex Clark with some of the data from ChEMBL as part of our efforts on open bayesian models which we have recently expanded to composite models.  The second figure below ranks some of these models based on the score derived from these ChEMBL derived Bayesian models. Several of the top scoring human targets include macrophage stimulating protein receptor, caspase-3, phosphoglycerate kinase, Dynamin 1. I must stress these are PREDICTIONS..

These high scores for many protein targets in humans could suggest the molecule is highly promiscuous and there may not be a single pathway interfered with. Vesicular acetylcholine transporter is slightly lower down in the list which also makes you wonder how many GPCRs might be impacted too. For now this is all idle speculation until we hear more about exactly what happened. Perhaps this compound could be profiled both computationally and experimentally to answer these questions of what the target/s of the toxicity are.

 

IMG_0596

 

 

predictions

4 comments

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  1. Alex Clark says:

    See http://cheminf20.org/2016/01/16/panel-of-bayesian-screening-for-bia-10-2474/ for link to the full page.

  2. sean says:

    Very sad to hear that one of the trial subjects passed away

  3. Lauren says:

    Interesting, but does not explain why on earth the the rats dogs, and monkeys did not exhibit any dramatic toxicities. This is a well known PHARMA company who appears to have done GLP standard toxicology exposures in several (more than minimally required) species.
    It sounds awfully unlikely that a drug would occur between multi dose cohorts.
    The effects in humans were relatively acute, and 3 species of animals saw drug longer and at higher levels.
    Is there a unique toxic metabolite? For 3 species to miss this is unthinkable.
    Are these effects on target showing (nearly) irreversible enzyme inactivation?
    It is feeling more like a inadvertent contaminant poisoning issue.

  4. sean says:

    Not sure the company was that well known – I had never come across it before. Why nothing picked it up before trial is obviously a major concern.

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