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Home»News»ACBI3 molecule offers new hope for targeting KRAS mutations in cancer
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ACBI3 molecule offers new hope for targeting KRAS mutations in cancer

healthtostBy healthtostSeptember 23, 2024No Comments4 Mins Read
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Acbi3 Molecule Offers New Hope For Targeting Kras Mutations In
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KRAS is the most mutated gene in cancer with mutations occurring in 17%-25% of all cancers, affecting millions of patients worldwide. It plays a key role in tumor growth, as it is important in promoting the uncontrolled proliferation of cancer cells. Targeting KRAS function is a primary focus of cancer drug discovery. However, currently approved treatments can only address one of the many mutations in the KRAS gene, called G12C, leaving more than half of patients with KRAS-driven cancers without a targeted treatment option.

The ACBI3 molecule developed by interdisciplinary teams in the laboratory of Professor Alessio Ciulli and Boehringer Ingelheim is based on a class of small molecules called Proteolysis Targeting Chimeras (PROTACs). ACBI3 has been shown to rapidly eliminate 13 of the 17 most common KRAS mutants with high potency and selectivity. KRAS degradation by ACBI3 was also more effective than using KRAS small molecule inhibition and induced efficient tumor regression in mouse models, validating KRAS degradation as a novel therapeutic concept.

It is exciting to work with Boehringer Ingelheim to explore a new therapeutic avenue for so many cancer patients in need.”


Professor Ciulli, Director of CeTPD, corresponding author of the study

“By joining forces with external partners who share our vision and desire for new drug innovation, and scientific leaders such as Professor Ciulli, one of the world’s pioneers in PROTACs and molecular adhesives, we can explore the full potential of new therapeutic avenues”. said Dr. Peter Ettmayer, co-corresponding author on the study and head of Drug Discovery Vienna at Boehringer Ingelheim.

A new way to fight cancer cells

PROTACs represent a new class of drug candidates with the potential to target cancer targets previously thought to be ‘unresectable’ by degrading them.

PROTACs are formed from small molecules with two ends. A “tooth” binds to the target protein that causes the disease. The other “tooth” recruits a protein called E3 ligase that is part of the cell’s natural disposal system (the ubiquitin-proteasome). Once in close proximity, the E3 ligase tags the target protein, marking it as “expired” so that it is then rapidly degraded by the ubiquitin proteasome.

Discovering ACBI3

To arrive at this complex, the team, led by Johannes Popow, Christiane Kofink and Andreas Gollner at Boehringer Ingelheim in Vienna and William Farnaby at Dundee (co-first authors) set out to directly target as wide a range of oncogenes as possible. KRAS mutations by rationally designing knockdown agents for them, rather than attempting to inhibit them, which is the most commonly used approach used for cancer targets.

Starting with high-quality small molecule “teeth” for KRAS at one end, attached to the E3 protein von Hippel-Lindau ligase (VHL) at the other end, they identified a first compound that showed promise in bringing the two proteins together. close to being “stuck” together, a feature often referred to as “molecular glue”. This offered the team an attractive starting point for further research.

The team was able to co-crystallize the three components KRAS, PROTAC and VHL. Using X-ray crystallography they were able to visualize the structure of this complex in atomic detail, helping them understand how the small molecule was able to recruit the two proteins together. Based on this understanding, the team was able to improve the compound and enhance its activity as a degrader step by step, in a rational and focused manner.

We join forces with the global scientific community

Importantly, Boehringer Ingelheim plans to make the KRAS knockdown compound ACBI3 freely available to the scientific community through the opnMe® portal with no strings attached, which could catalyze future research on this important target.

opnMe® is Boehringer Ingelheim’s open science portal. It leverages innovation by connecting the best experts from around the world with Boehringer scientists. opnMe® promotes independent scientific innovation with free high-quality molecules for research purposes, research funding for new ideas on selected molecules or scientific questions, and PostDoc grants.

“Sharing this tool with the wider research community will allow scientists to study the consequences and potential of degrading a key protein that drives cancer with the ultimate goal of transforming the lives of people living with cancer,” added Dr Ettmayer.

Source:

Journal Reference:

Popow, J., et al. (2024). Targeting cancer with small molecule pan-KRAS knockdowns. Science. doi.org/10.1126/science.adm8684.

ACBI3 cancer hope KRAS molecule mutations offers Targeting
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15 easy ways to get 20 grams of protein (Personal Trainer Guide)

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