Chemical probes for Open Science

31 May 2018

Interview with 

Susanne Müller-Knapp, Goethe University, Frankfurt

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In the domain of cell biology it’s proteins that make the world go around, and if you want to know what a specific protein does, one of the options open to you is to try to turn it off. And there are compounds on the market that purport to do just that. The problem is that these inhibitor molecules are notoriously “dirty” in their actions and can produce off-target effects that can distort the results. Now a number of pharmaceutical companies that do have good quality protein inhibitors, probes and control molecules have got together to share their compounds with the scientific community to try to clean up the published literature. Chris Smith spoke with Susanne - Müller-Knapp, at the Goethe University in Frankfurt, where she is heading up the initiative…

Susanne - These compounds they come from the pharmaceutical industry, and for many years the pharmaceutical industry has been rather closed, and so these high quality compounds they have generated existed but they have not been available. In more recent years these compounds are available through commercial vendors, but not all of them; many of them are just hidden in patents, and if you don't have any chemical synthesis at hand, although this may be a very useful tool compound, the common biologist do not have access to these compounds. Importantly, also what we are providing in this project is a control compound very similar in the chemical structure to the actual compound but lacks the on-target effect of our probe compound. Only with this pair can say with certainty that you're actually hitting your target or the effect you are seeing is owing to inhibition or activation of your target of interest.

Chris - So this is going to be powerful then, because you'll be able to enable scientists to do new science - looking at these targets - but also to clean up our existing data because we can use these non-active versions to see what "dirty" effects we may have accidentally attributed to these proteins in the past?

Susanne - Absolutely, and the literature is full of this contradicting results wrongly assigned to a target protein due to not well-characterized inhibitors. So often an inhibitor is claimed to be specific but has only been tested in a handful of compounds. But we now provide compounds that are very widely profiled - not only against the target, the target family, but also against known pharmacologically-active targets.

Chris - So how did you persuade the pharmaceutical industry to share these compounds with you so you can make them available like this?

Susanne - This was not our idea. It originates from the pharma industry themselves, and that's because pharma industry is reading the same literature as all academics. That means ideas for new targets to develop drugs originate from the literature and studies for sample from Bayer or Amgen has shown that when they try to reproduce published data, very often they fail to do so.

Chris - So actually, by sharing and sharing alike amongst the community everyone gets a benefit not just your own company but if you borrow everyone else's data you're benefiting from their insights too?

Susanne - Yes that's correct. It's basically to increase the knowledge and to increase the quality of science.

Chris - Now what's the actual mechanism by which you're doing this. How do people find the compound they need and then obtain the compound so that they can then deploy it at their experiments?

Susanne - We have generated a database, which we try to make very simple, so that you can find your compound; you can find at one glance the important characterisation data; we provide guidance on how to use the compound, because even the best characterized compound will give wrong results if you use it at too high a concentration; and we also have in the database a very simple way how to obtain the data: you basically click that you want to obtain the compound, and we will send the compound, including controls, to you.

Chris - Now how many compounds do you have on your database at the moment, and what mechanism is there to make sure that the library grows? Because, obviously, you've got a starting point: you have a certain number of chemicals - but there are going to be new proteins discovered, new functions discovered, and therefore new inhibitors discovered. So what's your plan for growth?

Susanne - So currently there are about 24 compounds in the database. This is from the first wave of compounds. There is a second meeting now, in June, where the second wave of compounds will be evaluated. So we hope to have about 70 compounds by the end of next year, all profiled and approved by the scientific committee, also, with this article, there is basically an appeal for other people to join the project to provide compounds, and it has already been successful. So I'm currently already negotiating with academic as well as new industry partners who are willing to provide their quality compounds with us.

Chris - How are you going to make sure it's sustainable, because it can't be cheap to be maintaining this archive of chemicals, growing the archive of chemicals, and then when someone wants some of them sending them off all over the world to researchers who want to use them?

Susanne - That is indeed a so far unsolved problem. We have had very generous support of the PDSP. The NIH has supported us. Even companies like Discoverx - Eurofins - have supported us. But we don't have a final solution yet how we will finance this project. So we are constantly talking to funders and I hope they understand that, with this way, we can improve the quality of research...

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