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Study polypharmacology earlier in drug discovery, say researchers

Study polypharmacology earlier in drug discovery, say researchers



Polypharmacology – the ability of a drug to affect more than one protein – should be studied early in drug discovery and constantly monitored on a drug’s path to the clinic, leading researchers believe.


New research demonstrates the importance of assessing polypharmacology from the outset to avoid undesirable off-target effects or potentially in future even to deliberately hit two or more desired targets at once.


The new study by scientists at The Institute of Cancer Research, London, used computational and experimental approaches to study the polypharmacology of a class of drugs called Hsp90 inhibitors, determining whether these inhibitors also affected another group of proteins, kinases.


It showed the potential for the polypharmacology of a prototype drug to change as it is optimised for activity against one particular protein through the drug discovery journey – and reinforced the importance of keeping a careful track of which additional proteins a drug is hitting from the start.


Drugs with significant polypharmacology are likely to be less specific in their effects on cells than those that only hit a single protein. The consequences of off-target effects are hard to predict and could include unexpected side effects and difficulty in understanding a drug’s real mechanism of action, or potentially the increased effectiveness of a drug if it was able to hit multiple cancer targets.


Scientists at The Institute of Cancer Research (ICR) looked at all the kinases affected by Hsp90 inhibitors, in research published in Cell Chemical Biology today (Tuesday) and largely funded by Wellcome.


Although these inhibitors were initially developed to inhibit the activity of one cancer-driving protein, Hsp90, the researchers found that some of the drugs were ‘multi-tasking’, affecting several kinases as well as Hsp90. They also showed that the kinases affected changed during the discovery and development of the drugs.


Hsp90 is a protein chaperone – meaning it helps other proteins to fold correctly in a cell – and is therefore essential for the proper functioning of many biological systems.


Hsp90 works with hundreds of client proteins, including several potential cancer drug targets, proteins involved in Alzheimer’s disease and viral proteins from SARS-CoV-2. Hsp90 inhibitors have entered clinical trials for the treatment of cancer and also for Alzheimer’s disease and Covid-19.


In the new study, the researchers studied six different Hsp90 inhibitors from different chemical families. Two, ganetespib and luminespib, showed significant off-target effects, meaning they affected other proteins as well as Hsp90. 


The scientists used computational approaches to predict the kinase polypharmacology of all six inhibitors and confirmed the predictions through experimental laboratory analysis. Luminespib and ganetespib showed off-target effects on several kinases, including some known to be involved in cancer development.


Kinases move phosphate groups onto proteins, affecting the activity of the protein. They play a key role in metabolism as well as cell signalling and are potential targets for many cancer drugs.


Importantly, the computational ‘in silico’ methods predicted half of the off-target effects found in the lab for both ganetespib and luminespib – underlining the usefulness of computational biology in drug discovery studies of this type.


For luminespib, the ‘hit’ compound and two ‘lead’ compounds – previous iterations of the molecule that became the drug – are publicly available, and so the researchers were also able to study how the off-targets evolved during the discovery of this drug. 


The researchers found that the off-target effects of luminespib changed significantly as the molecule was optimised. Unexpectedly, the final drug, luminespib, had significantly more off-targets than the lead compounds, and these included kinases that were not affected by the original hit compound.


The finding that the polypharmacology of a drug can change during the course of drug discovery suggests that off-target effects should be monitored from a much earlier stage.


The researchers believe that understanding a drug’s polypharmacology will be essential to be able to properly investigate and establish its mechanism of action. It should be possible to design out unwanted off-target effects, or potentially in future drugs could be designed to deliberately hit two or more desired targets at once, in order to pack a stronger punch than just hitting a single protein.


Study lead author Dr Albert Antolin, Sir Henry Wellcome Postdoctoral Fellow at The Institute of Cancer Research, London, said,


“The polypharmacology of a drug can influence the effects it has on cells, and the way it operates as a treatment. We found, to our surprise, that the polypharmacology of drug candidates created to target the protein chaperone Hsp90 changed during the drug discovery journey – with later-stage versions of the drug regaining off-target effects, and also gaining new effects different from earlier iterations.


“Our study underlines the importance of investigating off-target effects earlier in drug discovery, to be aware of potentially negative effects, and perhaps even to be able to exploit the benefits of off-target effects. It also demonstrates the growing value of in silico, computational methods in drug discovery.”


Study leader Professor Bissan Al-Lazikani, Head of Data Science at The Institute of Cancer Research, London, said:


“The systematic study of polypharmacology needs to become a crucial part of drug discovery. As computational approaches continue to improve, we can better predict how drugs will behave across the whole proteome, with an opportunity to understand much better how they exercise their effects on cells. 


“Our new research underlines the potential of computational techniques to help discover off-target effects that may interfere with a drug’s specificity, and even opens up future opportunities to design ‘multi-tasking’ drugs that hit more than one target involved in disease.”

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Last Updated: 02-Jun-2021