Small molecule drug shows potential for difficult-to-treat cancers

Experts from the university’s Centre for Targeted Protein Degradation (CeTPD), in collaboration with scientists from Boehringer Ingelheim, have developed a groundbreaking small molecule drug, a “protein degrader”.

This molecule, called ACBI3, could potentially lead to new therapies that are independent of the KRAS mutation type, thus improving outcomes for all patients with cancer caused by KRAS mutations. The research results were published in the prestigious journal Science.

Possible treatment for millions of cancer patients

KRAS is the most commonly mutated gene in cancer. Mutations occur in 17-25% of all cancers and affect millions of patients worldwide. It plays a crucial role in tumor growth as it is important for the uncontrolled spread of tumor cells. Targeting KRAS function is a major focus of cancer drug research. However, currently approved treatments can only treat one of many KRAS gene mutations, G12C, leaving more than half of patients with KRAS-related cancers without a targeted treatment option.

Developed by multidisciplinary teams in the laboratory of Professor Alessio Ciulli and Boehringer Ingelheim, the ACBI3 molecule 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 knockdown by ACBI3 was also more potent than using small molecule KRAS inhibition and induced effective tumor regression in mouse models, confirming KRAS knockdown as a novel therapeutic concept.

“It is exciting to collaborate with Boehringer Ingelheim to explore a new therapeutic approach for so many cancer patients in need,” said Professor Ciulli, Director of CeTPD and corresponding author of the study.

“By joining forces with external partners who share our vision and drive to develop new medicines, and with leading scientists such as Prof. Ciulli, one of the world pioneers in the field of PROTACs and molecular adhesives, we can unlock the full potential of novel therapeutic approaches,” said Dr. Peter Ettmayer, co-author of the study and Head of Drug Discovery Vienna at Boehringer Ingelheim.

Fighting tumor cells in new ways

PROTACs represent a new class of potential drugs that have the potential to target cancer targets that were previously considered “drug-untreatable.”

PROTACs are made up of two-pronged small molecules. One “prong” binds to the disease-causing target protein. The other “prong” recruits a protein called E3 ligase, which is part of the cell's natural waste disposal system (the ubiquitin proteasome). Once they are in close proximity, the E3 ligase marks the target protein and labels it as “expired,” so it is then rapidly degraded by the ubiquitin proteasome.

Discover ACBI3

To arrive at this substance, the team, jointly led by Johannes Popow, Christiane Kofink and Andreas Gollner at Boehringer Ingelheim in Vienna and William Farnaby in Dundee (co-first authors), set out to directly attack as broad a spectrum of oncogenic KRAS mutations as possible by specifically developing degraders for these mutations, rather than trying to inhibit them, which is the most commonly used approach for cancer targets.

Starting with high-quality small molecules that form “tines” for KRAS at one end and are linked to the protein E3 ligase von Hippel-Lindau (VHL) at the other end, they identified a first compound that showed great promise for bringing the two proteins closer together in a way that “sticks” them together, a property often referred to as “molecular glue.” This provided the team with an attractive starting point for further investigation.

The team managed to crystallize the three components KRAS, PROTAC and VHL together. Using X-ray crystallography, they were able to visualize the structure of this complex in atomic detail and thus 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 increase its activity as a degrader step by step, in a rational and targeted manner.

Joining forces with the global scientific community

Importantly, Boehringer Ingelheim plans to make the KRAS degrader ACBI3 available to the scientific community free of charge and without any strings attached through its opnMe® portal, which could advance future research toward this important goal.

opnMe® is Boehringer Ingelheim's Open Science portal. It promotes 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 fellowships.

“By making this tool available to the entire research community, scientists can study the consequences and potential of degrading an important carcinogenic protein, with the ultimate goal of changing the lives of cancer patients,” added Dr. Ettmayer.

Reference:

Popow J, Farnaby W, Gollner A, et al. Fighting cancer with small molecule pan-KRAS degraders. Science. 2024. doi: 10.1126/science.adm8684

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