Health
Potential breakthrough for hard-to-treat cancers
KRAS is the most mutated gene in cancer, occurring in 17%-25% of all cancers and affecting millions of patients worldwide. KRAS plays a critical role in tumor growth as it promotes the uncontrolled proliferation of tumor cells. Targeting KRAS function is a major focus in cancer drug discovery. However, currently approved therapies only address one of the many KRAS gene mutations, called G12C, leaving more than half of patients with cancers driven by KRAS without targeted therapeutic options.
The molecule ACBI3, developed by Prof. Alessio Chiuri and his multidisciplinary team in the laboratory at Boehringer Ingelheim, is based on a class of small molecules called proteolytic targeted chimeras (PROTACs). ACBI3 has been demonstrated to rapidly eliminate 13 of the 17 most common KRAS mutations with high potency and selectivity. KRAS degradation by ACBI3 was more effective than using KRAS small molecule inhibition and induced effective tumor regression in mouse models, demonstrating that KRAS degradation is a new therapeutic concept.
“We are very pleased to collaborate with Boehringer Ingelheim to explore new therapies for the many cancer patients in need,” said Professor Chiuri, corresponding author of the study and Director of CeTPD.
“Joining forces with external partners who share our vision and drive to develop new medicines and with scientific leaders like Professor Ciulli, one of the global pioneers in PROTACs and molecular adhesives, allows us to explore the full potential of new therapeutic approaches,” said Dr Peter Ettmeyer, co-corresponding author of the study and Head of Drug Discovery Vienna at Boehringer Ingelheim.
A new way to fight tumor cells
PROTACs are a new class of drug candidates that have the potential to treat cancers by degrading targets previously considered “untreatable.”
PROTACs consist of a small molecule with two branches. One branch binds to a target disease-causing protein. The other branch recruits a protein called an E3 ligase, which is part of the cell's natural disposal system (the ubiquitin proteasome). Once in close proximity to the target protein, the E3 ligase labels the protein as “expired,” making it eligible for rapid degradation by the ubiquitin proteasome.
Discovery of ACBI3
To arrive at this compound, the research team, co-led by Johannes Popov, Christiane Kofik, and Andreas Gollner of Boehringer Ingelheim in Vienna, and William Farnaby of Dundee (co-first author), aimed to directly target the widest range of oncogenic KRAS mutations possible by rationally designing their degraders, without attempting inhibition – the most common approach to cancer targeting.
Starting with a high-quality small molecule “nub” for KRAS on one end and the E3 ligase von Hippel-Lindau (VHL) protein on the other, the researchers identified the first compound that showed great promise for bringing the two proteins in close proximity and “sticking” them together — a feature they call “molecular glue.” This provided the research team with an attractive starting point for further investigation.
The team successfully co-crystallized the three components – KRAS, PROTAC, and VHL. Using X-ray crystallography, they were able to visualize the structure of this complex down to the atomic level, helping them understand how the small molecule is able to recruit the two proteins together. Based on this understanding, the team was able to refine the compound, increasing its activity as a degrader in a rational, focused, step-by-step manner.
Joining forces with the global scientific community
Importantly, Boehringer Ingelheim plans to make the KRAS degrading compound ACBI3 freely available to the scientific community without any restrictions through the opnMe® portal, which may facilitate future research into this important target.
opnMe® is Boehringer Ingelheim's open science portal. It fosters innovation by connecting Boehringer scientists with the best experts from around the world. opnMe® fosters independent scientific innovation with free high-quality molecules for research purposes, research funds for new ideas on specific molecules and scientific questions, and postdoctoral grants.
“Sharing this tool with the entire research community will enable scientists to study the impact and potential of degrading key cancer-causing proteins, with the ultimate goal of transforming the lives of cancer patients,” Dr. Ettmeyer added.
|
Sources 2/ https://www.sciencedaily.com/releases/2024/09/240923121349.htm The mention sources can contact us to remove/changing this article |
What Are The Main Benefits Of Comparing Car Insurance Quotes Online
LOS ANGELES, CA / ACCESSWIRE / June 24, 2020, / Compare-autoinsurance.Org has launched a new blog post that presents the main benefits of comparing multiple car insurance quotes. For more info and free online quotes, please visit https://compare-autoinsurance.Org/the-advantages-of-comparing-prices-with-car-insurance-quotes-online/ The modern society has numerous technological advantages. One important advantage is the speed at which information is sent and received. With the help of the internet, the shopping habits of many persons have drastically changed. The car insurance industry hasn't remained untouched by these changes. On the internet, drivers can compare insurance prices and find out which sellers have the best offers. View photos The advantages of comparing online car insurance quotes are the following: Online quotes can be obtained from anywhere and at any time. Unlike physical insurance agencies, websites don't have a specific schedule and they are available at any time. Drivers that have busy working schedules, can compare quotes from anywhere and at any time, even at midnight. Multiple choices. Almost all insurance providers, no matter if they are well-known brands or just local insurers, have an online presence. Online quotes will allow policyholders the chance to discover multiple insurance companies and check their prices. Drivers are no longer required to get quotes from just a few known insurance companies. Also, local and regional insurers can provide lower insurance rates for the same services. Accurate insurance estimates. Online quotes can only be accurate if the customers provide accurate and real info about their car models and driving history. Lying about past driving incidents can make the price estimates to be lower, but when dealing with an insurance company lying to them is useless. Usually, insurance companies will do research about a potential customer before granting him coverage. Online quotes can be sorted easily. Although drivers are recommended to not choose a policy just based on its price, drivers can easily sort quotes by insurance price. Using brokerage websites will allow drivers to get quotes from multiple insurers, thus making the comparison faster and easier. For additional info, money-saving tips, and free car insurance quotes, visit https://compare-autoinsurance.Org/ Compare-autoinsurance.Org is an online provider of life, home, health, and auto insurance quotes. This website is unique because it does not simply stick to one kind of insurance provider, but brings the clients the best deals from many different online insurance carriers. In this way, clients have access to offers from multiple carriers all in one place: this website. On this site, customers have access to quotes for insurance plans from various agencies, such as local or nationwide agencies, brand names insurance companies, etc. "Online quotes can easily help drivers obtain better car insurance deals. All they have to do is to complete an online form with accurate and real info, then compare prices", said Russell Rabichev, Marketing Director of Internet Marketing Company. CONTACT: Company Name: Internet Marketing CompanyPerson for contact Name: Gurgu CPhone Number: (818) 359-3898Email: [email protected]: https://compare-autoinsurance.Org/ SOURCE: Compare-autoinsurance.Org View source version on accesswire.Com:https://www.Accesswire.Com/595055/What-Are-The-Main-Benefits-Of-Comparing-Car-Insurance-Quotes-Online View photos
to request, modification Contact us at Here or [email protected]
 |
 |
 |
