by Researchers from the Center for Genomic Regulation in Barcelona, Spain, and the Wellcome Sanger Institute near Cambridge, UK, have made a groundbreaking discovery by identifying the allosteric control sites in the KRAS protein. These sites have proven to be highly sought-after targets for drug development, as they represent secret vulnerabilities that can be exploited to control the effects of one of the leading causes of cancer. The study, published in the journal Nature, presents the first complete map of control sites for any protein.
KRAS is one of the most commonly mutated genes in various types of cancer. It is found in approximately one in 10 human cancers, with higher prevalence in more lethal forms such as pancreatic and lung cancers. Due to its spherical shape and lack of a suitable target site for drug intervention, KRAS has been given the moniker “Death Star” protein. Hence, since its discovery in 1982, KRAS has been considered “undruggable.”
Until now, the only effective method to control KRAS was by targeting its allosteric communication system. These molecular signals function through a remote-control lock and key mechanism. To control a protein, a key in the form of a chemical compound or drug is required to open an active site lock. Additionally, proteins can be influenced by a secondary lock called an allosteric site, which is located elsewhere on the protein’s surface.
When a molecule binds to an allosteric site, it induces a change in the protein’s shape, thereby altering its activity or its ability to bind to other molecules. This is achieved by modifying the internal structure of the main lock.
Allosteric sites are considered preferable for drug development due to their higher specificity, which reduces the likelihood of side effects. They can also modulate the activity of a protein more subtly, allowing for fine-tuning of its function. Drugs targeting allosteric sites generally offer enhanced safety and efficacy compared to those targeting active sites. However, allosteric sites have proven to be notoriously difficult to identify. Despite over four decades of research, tens of thousands of scientific publications, and more than 300 published structures of KRAS, only two drugs, sotorasib and adagrasib, have been approved for clinical use. These drugs work by binding to a pocket adjacent to the active site, inducing an allosteric conformational change in the protein that prevents its activation.
The development of a functional drug against KRAS has taken decades, mainly due to the lack of tools for identifying allosteric sites on a large scale. Researchers were essentially searching for therapeutic target sites blindly. However, this study introduces a novel approach that enables systematic mapping of allosteric sites for entire proteins. According to Dr. André Faure, a staff scientist at the Center for Genomic Regulation and co-author of the study, this approach sheds light on numerous ways to control a protein and significantly accelerates drug discovery efforts for KRAS.
The authors of the study employed a technique called deep mutational scanning to construct a map of allosteric sites. They created over 26,000 variations of the KRAS protein, altering only one or two amino acids at a time. The team then examined how these different variations of KRAS interacted with six other critical proteins involved in causing cancer. AI software was utilized to analyze the resulting data, detect allostery, and identify the locations of both known and novel therapeutic target sites.
A major advantage of this method is its scalability. In this study alone, over 22,000 biophysical measurements were conducted, surpassing the total number of measurements made for all proteins prior to the utilization of recent advancements in DNA sequencing and synthesis methodologies. This acceleration demonstrates the power and potential of the approach, as explained by Chenchun Weng, the first author of the study and a postdoctoral researcher at the Center for Genomic Regulation.
The technique revealed that KRAS possesses a greater number of robust allosteric sites than previously anticipated. Mutations in these sites inhibited the protein’s binding to all three of its primary partners, indicating the possibility of broadly inhibiting KRAS activity. Of particular interest are the allosteric sites located in four accessible pockets on the surface of the protein. These pockets represent promising targets for future drug development.
The study highlights one specific pocket, known as “pocket 3,” as particularly intriguing. This pocket has received minimal attention from pharmaceutical companies in the past due to its distance from the active site of KRAS.
Additionally, the researchers discovered that minor alterations in KRAS can significantly impact its interactions with its partners, causing the protein to favor one over another. This finding holds significant implications, as it could lead to new strategies for controlling the abnormal activity of KRAS without hindering its normal function in non-cancerous tissues.
Preserving the normal versions of KRAS would result in fewer side effects and safer and more effective treatments. Furthermore, the knowledge gained from this study could further elucidate the biology of KRAS and provide insights into its behavior in different scenarios, which is crucial for determining its role in various types of cancer.
This groundbreaking study marks the first of its kind to provide a comprehensive map of allosteric sites for an entire protein across any species. The research demonstrates that with the right tools and techniques, vulnerabilities can be uncovered for numerous medically significant proteins that were previously deemed “undruggable.”
According to Dr. Ben Lehner, the senior author of the study from the Center for Genomic Regulation and the Wellcome Sanger Institute, the primary challenge in medicine lies in not identifying the proteins responsible for diseases but rather in knowing how to control them. This study represents a novel strategy for targeting these proteins and expediting the development of drugs to regulate their activity. Targeting allosteric sites offers the potential for safer and more effective treatments compared to current options.
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1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
Money Singh is a seasoned content writer with over four years of experience in the market research sector. Her expertise spans various industries, including food and beverages, biotechnology, chemical and materials, defense and aerospace, consumer goods, etc.
