Scientists tackle the issue of “nuisance compounds”

An international consortium of world-leading scientific investigators, including Monash University, are developing a “nuisance compound” toolset, which will enable global researchers to distinguish the good from the bad when screening for compounds during drug discovery efforts.

Poor quality compounds and compounds that interfere with bioassay readouts are often colloquially referred to as “nuisance compounds” because they generally do not represent viable starting points for drug optimisation and development.

When screening large numbers of compounds against therapeutic targets, nuisance compounds show promising activity in these primary screens, but demonstrate no activity during subsequent hit qualification or progression efforts.

The Nuisance Compound Tool Consortium was formed to address the issue of these resource-sapping compounds.

The Consortium’s Monash University contingent is represented by renowned medicinal chemist and Director of the Australian Translational Medicinal Chemistry Facility, Professor Jonathan Baell, who has been a leading voice on the issue of nuisance compounds for a number of years.

“One of the best ways to end up with a first-in-class drug is to run high throughput assays to test large numbers of random compounds - to essentially sieve the wheat from the chaff - and land on good chemical starting points for optimisation and drug development.”

“This assay technology is increasingly accessible, but it can be problematic when the screens identify many compounds that are subversive and therefore not able to progress – in other words, a nuisance.

“Our hope is that our toolset of nuisance compounds will end up being a positive game changer for the scientific community, which is currently full of  papers centred around nuisance compounds that are futile,” said Professor Baell.

The Consortium, which was formed in 2019 and has now been legally formalised, is made up of seven Principal Investigators from Monash, AstraZeneca, Novartis, the Broad Institute of MIT and Harvard, Eli Lilly and Company, the University of Minnesota and the National Centre for Advancing Translational Sciences at the US. National Institutes of Health.

The initial phase of the consortium will see each collaboration site develop a proposed list of nuisance compounds which will be shared within the consortium. The shared data will be used to draft a virtual nuisance compound library based on a collaborative analysis of the data by consortium members.

Moving into the next phase, the members will work together to develop a physical version of the nuisance compound library. This will be accessible by researchers worldwide to help them understand in what ways their own assays might be susceptible to specific types of nuisance compounds, with the goal to stamp out the propagation of compounds that have proven to be so costly.

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