The pain of drug discovery

A recent paper in J Med Chem highlights again the perils and pitfalls of early stage drug discovery activities when we are searching for that elusive early chemical matter which has the true potential to be polished up into drug candidate gems. The group describes the HTS output looking for inhibitors of DNA cytosine deaminases APOBEC3A (A3A) and APOBEC3G (A3G), which are interesting targets under investigation in a range of labs following data linking them to mutation and evolution in cancer and HIV-1.

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The group in the University of Minnesota screened just over 20k compounds from a range of commercial library sources in a fluorescence-based assay and identified a hit that they found particularly encouraging, with micromolar target potency.

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This hit had the quinolone-furan sub-structure that is present in a range of members of the various libraries, which coupled with emergent SAR in the series and all the usual checks of confirming hits from repurified, new solid stocks, gave them confidence in the start point.

However, having launched into a hit to lead chemical programme, life started to turn sour, with the finger of suspicion quickly pointing at the inherent stability of the hit structure itself in solution. They essentially discovered that fresh solid preparations were inactive in their assay system but activity was restored over time as the solution stocks aged…….The story is all too familiar across the early hit landscape, and the rest of the paper is then taken up with a description of the various instability pathways and decomposition routes (some highlighted in graphical abstract above) – principally via aerial oxidation of the furan followed by Baeyer-Villiger rearrangement and on to a variety of nasty looking species.

The main point of the publication is then to make furans, and specifically this quinolone-furan sub-structure, sit on the naughty step along with the other PAINS and associated promiscuous/unstable/frequent-hitting structures. Whilst a number of us, I think, would already have suspicions about the stability of furans (despite being components of marketed drugs such as lapatanib), the open disclosure of unsuccessful hit finding campaigns and ‘lessons learned’ in these sorts of papers is to be applauded. Whilst the number of papers highlighting these issues is increasing at a very rapid rate, there are still many inappropriate chemical tools in circulation and widespread use and I fear that we may currently be preaching to the (mainly) converted. Hopefully, initiatives over wider public sharing of these pitfalls will provide some further integration of this knowledge into the wider community.

Blog written by Simon Ward