Biological Results for First Set of Compounds

The screening data from three separate labs have been obtained for the first set of compounds on the project. Data were obtained from the Ralph Lab at the University of Melbourne, and a second data set was provided just before Christmas by the Avery Lab at Griffith University. Yesterday the third set was provided by GSK Tres Cantos in Spain, who originally discovered the hits we're starting with. The current list of available compounds in this open project is here, with those that have been evaluated by at least one lab indicated in the relevant column.

Having data on the same compounds from three labs using different screening methods is useful as it provides contrasting ways of assaying effectiveness. In any given screening experiment on this project it's going to be important to include known actives, so that we have benchmarks, and this was done in these cases. It's also very important to be 100% sure about the effectiveness of a compound before we become too attached to it...

The data (below, but all available through the relevant lab book) show that the original TCAMS compounds are certainly active, though perhaps not quite as active as suggested by the original screen. Paul Willis at MMV had suggested we also check out some "near neighbors" of these compounds that were in the original data set. We made a couple and one (a novel compound with the code PMY 14-1, shown below and synthesized here) has shown promising activity in all three screens, with Avery/GSK IC50s coming back as low nanomolar. (Note that this project will never involve patents or closed data, giving us the freedom to discuss the compounds freely.)

What's next? In the short term: We're waiting for confirmation of the Melbourne data via a re-run of some of the experiments. But what we need is an expert qualitative assessment of these bioactivity data by someone familiar with such screening assays. Either in comments below this post, or on G+, not by email. First item of business in the lab is to generate a few variants of PMY 14-1. We already have some new relevant compounds and are now planning others. What should we make - i.e. how ought we to change PMY 14-1? Sanjay Batra has students who are about to make steric variations in the aryl pyrrole, and these could then be employed in the synthesis of PMY 14-1 variants, for example, but shouldn't we also be interested in changes in the "upper half" of the molecule?

In the long term: It would be good to find other labs which already have analogous compounds to the actives. Paul and Zoe found a paper from the Roberts lab at Scripps describing a number of such compounds, and I will write to them to ask whether they are interested in having the compounds be screened for their antimalarial activity. If anyone knows of any other possible sources, that would be great, since using existing compounds saves a lot of time in the lab.