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

Experts from the University of Dundee’s Centre for Targeted Protein Degradation (CeTPD), in collaboration with scientists from Boehringer Ingelheim, have developed a revolutionary small molecule drug, a ‘protein degrader’.

The KRAS gene is the most mutated gene in cancer. Mutations affect 17 to 25% of cancers and affect millions of patients worldwide. It plays a crucial role in tumor growth, as it is important for promoting the uncontrolled proliferation of tumor cells.

Targeting KRAS function is a major goal of cancer drug discovery. However, currently approved treatments can only address one of many KRAS mutations, called G12C, leaving more than half of patients with KRAS-driven cancers without targeted treatment options.

The ACBI3 molecule developed by multidisciplinary teams from Professor Alessio Ciulli’s laboratory and Boehringer Ingelheim is based on a class of small molecules called PRoteolysis TArgeting Chimeras (PROTACs). ACBI3 was shown to rapidly eliminate 13 of the 17 most common KRAS mutants with high potency and selectivity.

KRAS degradation by ACBI3 was also more efficient than using small molecule KRAS inhibition and induced effective tumor regression in mouse models, validating KRAS degradation as a novel therapeutic concept.

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

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

The work is published in the journal Science.

PROTACs represent a new class of drug candidates with the potential to address cancer targets that were previously considered “undruggable” by degrading them.

PROTACs consist of two small molecules. One of the two “branches” binds to the target protein responsible for the disease. The other “branches” recruit a protein called an E3 ligase that is part of the cell’s natural clearance system (the ubiquitin-proteasome). Once in proximity, the E3 ligase marks the target protein as “stale,” so that it is then rapidly degraded by the ubiquitin-proteasome.

Discover ACBI3

To obtain this compound, the team, co-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 target as broad a range of oncogenic KRAS mutations as possible by rationally designing degraders for them, rather than trying to inhibit them, which is the most commonly used approach for cancer targets.

Starting with high-quality small molecules for KRAS at one end, linked to the E3 protein von Hippel-Lindau (VHL) ligase at the other end, they identified a first compound that showed great promise in bringing the two proteins together to the point of “gluing” them together, a characteristic often referred to as “molecular glue.” This gave the team an interesting starting point for further research.

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 smallest atomic detail, which helped 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 degrader activity 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 compound ACBI3 freely available to the scientific community through its opnMe portal, with no strings attached, which could catalyze future research into this important target.

opnMe is the open science portal of Boehringer Ingelheim. It fosters innovation by connecting top 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.

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