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New drug reveals a key mechanism to overcome resistance to protein degraders

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  • Protein degraders offer a novel approach to targeting undruggable diseases by hijacking the cell's degradation machinery.
  • Scientists at IRB Barcelona identify a promising drug, RBS-10, capable of selectively killing cells that are resistant to protein degraders, thus providing hope in overcoming such resistance.
  • Uncovering the pivotal role of the enzyme NQO1, this study sheds light on a key vulnerability in resistant cells and offers potential insights that could be useful for future cancer treatments.
     

Protein degraders, a novel approach in drug discovery, show promise to tackle diseases previously thought to be untreatable. Unlike traditional drugs that block specific protein functions, degraders alter the cell's natural degradation process so that it can remove disease-relevant proteins. 

However, resistance to these degraders is still an unsolved issue. A recent study led by Dr. Cristina Mayor-Ruiz and Dr. Antoni Riera at IRB Barcelona has made significant progress towards understanding and combating resistance to these innovative drugs.

 

 

Overcoming Resistance: a persistent challenge in cancer treatment

The development of resistance to cancer treatments is a significant obstacle for the effective management of the disease. As cancer cells reproduce quickly, they can adapt and become resistant to drugs over time, thereby rendering treatments ineffective. This issue is particularly problematic with protein degraders, which show great promise but are also susceptible to resistance.

In their study, the researchers tackled this challenge using the cellular model most resistant to protein degraders known to date. Their primary goal was to find a drug capable of specifically targeting and eliminating these resistant cells.

After an extensive chemical screening and optimisation process, the team identified a drug named RBS-10, which can selectively remove resistant cells and thus emerges as a promising solution to this pressing issue.


NQO1: an actionable vulnerability in resistant cells

To better understand how RBS-10 exerts its effects, the researchers delved into its mechanism of action. Using chemoproteomics, they pinpointed the enzyme NQO1 as the primary target of RBS-10

Interestingly, the resistant cellular model showed a significant increase in NQO1 expression. Further analysis through proteomics, metabolomics, and genetic approaches revealed interesting information: RBS-10 acts as a prodrug. This means that it is activated only after its metabolism by NQO1 in resistant cells.

"We felt like 'molecular detectives' in this project, making use of a repertoire of chemical biology approaches to discover that RBS-10 works as a prodrug. Our discoveries not only provide valuable molecular insights into RBS-10's mechanism of action but also have potential implications for the development of future therapies," commented Dr. Mayor-Ruiz.


Translating findings to clinical applications

As protein degraders continue to progress towards clinical applications, understanding resistance mechanisms is crucial. “Importantly, drugs in pre-clinical and clinical stages that work like RBS-10 may hold the key to addressing resistance to protein degraders in clinical settings,” concludes Dr. Riera.

First-authored by Bárbara Barbosa, Aikaterini Sfyaki and Sergi Rafael, this work is a significant milestone in the ongoing fight against resistance to protein degraders. With NQO1 identified as a useful player, the scientific community is one step closer to developing innovative strategies to combat resistance and enhance the effectiveness of cancer treatments.

 

Related article:
Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.
Bárbara M. G. Barbosa*, Aikaterini Sfyaki*, Sergi Rafael*, Ferran José-Duran, Joan Pous, Carolina Sánchez-Zarzalejo, Carles Perez-Lopez, Mar Vilanova, Marko Cigler, Marina Gay, Marta Vilaseca, Georg E. Winter, Antoni Riera# & Cristina Mayor-Ruiz#
Angewandte Chemie (2023) DOI: 10.1002/anie.202316730
 

About IRB Barcelona

The Institute for Research in Biomedicine (IRB Barcelona) pursues a society free of disease. To this end, it conducts multidisciplinary research of excellence to offer pioneering solutions to unresolved medical needs in cancer and other diseases related to ageing. It establishes technology transfer agreements with the pharmaceutical industry and major hospitals to bring research results closer to society and organises a range of science outreach activities to engage the public in an open dialogue. IRB Barcelona is an international centre that hosts 400 employees and more than 30 nationalities. Recognised as a Severo Ochoa Centre of Excellence since 2011, IRB Barcelona is a CERCA centre and member of the Barcelona Institute of Science and Technology (BIST).

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