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A breakthrough procedure for efficient and effective development

Revolutionising drug discovery

Discover how researchers have transformed the early stages of drug development with a ground-breaking test that identifies the most promising compounds. "Saving time and resources by focusing on the most potential compounds".


Researchers at the Centre for Cancer Drug Discovery at The Institute of Cancer Research (ICR), London have made a significant breakthrough in the field of drug discovery. Their new investigative procedure promises to revolutionize the early stages of drug development by making it more efficient and effective.


This ground-breaking test allows scientists to identify new biologically active compounds with the highest potential, saving valuable time and resources. Thanks to this procedure, researchers worldwide can now select only the most promising compounds to develop into effective medications.


The study, funded by Cancer Research UK, has been published in the prestigious Journal of Medicinal Chemistry, highlighting its importance and impact on the field.


A new approach to fragment-based drug discovery


Fragment-based drug discovery has become the standard method for identifying the starting point of a drug discovery program. Scientists screen libraries of compounds, known as fragments, to determine their interaction with a potential anti-cancer target.


Previously, scientists could only qualify the interactions between fragments and target proteins as a simple "yes" or "no". However, weak, or nonspecific interactions were challenging to evaluate accurately.


Now, thanks to this latest research, researchers have developed a quantitative approach to measure the strength of these interactions. By ranking the fragments based on their interaction strength, research teams can confidently identify the most active compounds to move forward in the drug development process.


This additional information allows scientists to refine the selected fragments by optimizing their shape, combining them with other fragments, or both. The result is a more streamlined and efficient drug discovery workflow.


Realising the potential of the new procedure


Dr. Maggie Liu, the first author of the study and a Senior Scientific Officer at the ICR, expressed confidence that this new procedure will become an integral part of the standard drug discovery workflow. The method is accessible to any team with the right equipment, providing a valuable tool for the wider drug discovery community.


The ICR has already started follow-up work on one of the identified fragments using this new test. They plan to utilize this procedure for all future projects, recognizing its potential to accelerate the development of life-saving drugs.


Compounds discovered from fragment-based drug discovery (FBDD) and their potential effects


FBDD has emerged as an effective strategy in drug discovery, leading to the identification of several compounds with promising potential, including:


1. Vemurafenib: FDA approved in 2011, Vemurafenib has shown efficacy against specific targets, potentially offering treatment options for certain conditions.


2. Venetoclax: Another FBDD-derived drug, Venetoclax, received FDA approval in 2016. It has demonstrated positive outcomes in clinical trials, indicating its potential as a therapeutic agent.


3. Pexidartinib: Approved in 2019, Pexidartinib is a fragment-derived drug that has exhibited promising effects against its intended targets.


4. Erdafitinib: Similarly, Erdafitinib, developed through FBDD, obtained FDA approval in 2019. It has shown potential in clinical trials, highlighting its significance as a therapeutic option.


5. Sotorasib: This compound, approved in 2021, is another example of a fragment-derived drug with potential therapeutic benefits against specific targets.


6. Asciminib: Lastly, Asciminib, also approved in 2021, is a fragment-based drug that has demonstrated efficacy in clinical trials, showcasing its potential as a therapeutic intervention.


These compounds represent a fraction of the molecules discovered through FBDD, and their effects vary depending on the specific targets they interact with. Further research and clinical trials are necessary to fully understand the therapeutic potential of these compounds and their broader impact on various diseases and conditions.


Testing the R2KD tool


Dr. Liu and her team successfully used the R2KD tool to identify new biologically active compounds. This tool utilizes a ligand-observed nuclear magnetic resonance (LONMR) approach, similar to an MRI scanner, to observe fragment interactions.


By measuring the transverse relaxation rate (R2) of the fragments, which indicates their speed in the solution, the researchers could determine the fragments' interaction with the target protein. They then applied a new mathematical formulation to calculate a binding affinity value (Kd) for each fragment and compare their Kd values. This allowed them to identify the fragments with the strongest interactions. The researchers named their test 'R2KD'; based on these steps. By using this method, scientists can now quantitatively determine the binding affinity of fragments, which helps in selecting compounds with the most potential for further development. This new procedure makes the early stages of drug discovery more efficient, saving time and resources by focusing on the most promising compounds.



Written by Sara Maria Majernikova


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