Sayak Banerjee, Amity University Kolkata
The scientists at the University of Leeds have discovered a new method of targeting a mutated protein, which is the reason behind most of the fatal cancers. The mutated form of RAS protein is often considered the “Death Star” since it has the potential to resist various treatments. Although RAS protein is essential for our health, the mutated form of RAS protein could be switched on for longer, resulting in tumour growth. This mutation is generally observed in around 54% of colon cancers and 96% of pancreatic cancers.
The RAS family comprises small GTPases, KRAS4A, KRAS4B, HRAS, and NRAS, which play an important role as bi-directional molecular switches. These four members switch between an inactive GDP-bound form and an active GTP-bound form. The mutated form of RAS protein usually activates the formation of tumours in the lungs, pancreas, and colon and the most recurrently affected member is KRAS. Therefore, RAS has been a potential therapeutic target for decades without any promising success in preclinical trials.
There has been a scarcity of clinically certified RAS-inhibitors due to the lack of druggable pockets to be able to be identified on the surface of RAS protein. One drug despite being approved for treatment can tackle only a few cancer types out of the total number of cancers induced by RAS. Lately, the research team from the University of Leeds’ School of Molecular and Cellular Biology has studied further to come up with wide-ranging options of treatments for many more patients and published their findings in the journal, Nature Communications.
One of the researchers stated that since the RAS protein or the Death Star is almost spherical and impenetrable in nature, it significantly prevents drugs from binding to it, thus inhibiting them. They used their Affimer biotechnology platform for the identification of druggable pockets. They found a minute cleft that could serve as an allosteric site for the new drugs other than the ones in development. The first pocket is situated between the Switch I and Switch II regions of RAS and various groups have developed compounds independently, mainly in the micromolar range. The second pocket is situated below the Switch II region and is incompletely formed in KRAS structures due to the absence of the inhibitor. The cleft is evident in some of those structures and has been recognized as a potential allosteric site.
They said that this study could pave the way for numerous disease targets excluding cancer. Any protein involved in any arbitrary disease could be probed efficiently for druggable pockets in the coming future. RAS is considered the Holy Grail of therapeutic targets because it is the cause of around 20-30% of all common cancers. It being previously stated as ‘undruggable’ enabled the scientists to exhibit the strong effect that their Affimer technology has brought about. They have found small molecules that bind to RAS at those pockets and this has given rise to the only series of RAS inhibitors presently in clinical trials.
This approach has opened the doors to not only give wider application to RAS-driven cancers but also act as potential drug discovery tools. The researchers mentioned that they would further study the development of these RAS-inhibitor drugs. They believe to put Leeds in the lead of the fight against cancer by extending more ways for targeting RAS in its early stages and eventually resulting in new treatments.
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Reference:
- Haza, K.Z., Martin, H.L., Rao, A. et al. RAS-inhibiting biologics identify and probe druggable pockets including an SII-α3 allosteric site. Nat Commun 12, 4045 (2021). https://doi.org/10.1038/s41467-021-24316-0
- The thumbnail image has been extracted from Servier Medical Art.
About author:
Sayak Banerjee is a 3rd year Biotechnology Engineering Student with great interest in Immunology and Molecular genetics. He is a creative scientific writer in Bioxone with an inclination towards gaining knowledge regarding various sections of Biotechnology and emphasizing himself in various wet lab skills.
Publications:
- https://bioxone.in/news/worldnews/car-t-cells-scientists-discover-on-off-switches-for-cell-immunotherapy/
- https://bioxone.in/news/worldnews/neutrophil-derived-nanovesicles-a-novel-drug-delivery-system/
- https://bioxone.in/news/worldnews/pig-to-human-heart-transplantation-a-solution-to-the-rarity-of-donor-organs/
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