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 crucial role in tumour growth, as it is important for driving uncontrolled proliferation of tumour cells. Targeting KRAS function is a primary focus of cancer drug discovery. However, currently approved treatments can only address one of many KRAS gene mutations, called G12C, leaving more than half of patients with cancers driven by KRAS without a targeted treatment option.
The molecule ACBI3 developed by multi-disciplinary 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 be able to rapidly eliminate 13 out of the 17 most common KRAS mutants with high potency and selectivity. KRAS degradation by ACBI3 was also more efficacious than using KRAS small molecule inhibition, and induced effective tumour regression in mouse models, validating KRAS degradation as a novel therapeutic concept.
“It is exciting to collaborate with Boehringer Ingelheim to explore a novel therapeutic avenue for so many cancer patients in need,” said Professor Ciulli, Director of the CeTPD, corresponding author of the study.
“By joining forces with external partners that share our vision and drive to innovate new medicines, and scientific leaders such as Prof. Ciulli, one of the world’s pioneers in PROTACs and molecular glues, we can explore the full potential of novel therapeutic avenues,” said Dr. Peter Ettmayer, co-corresponding author in the study and head of Drug Discovery Vienna at Boehringer Ingelheim.
A new way of fighting tumour cells
PROTACs represent a new class of drug candidates with the potential to tackle cancer targets, which were previously considered “undruggable,” by degrading them.
PROTACs are formed by two-pronged small molecules. One ‘prong’ binds to the target disease-causing protein. The other ‘prong’ recruits a protein called E3 ligase that is a part of the cell’s natural disposal system (the ubiquitin-proteasome). Once in close proximity, the E3 ligase tags the target protein, labelling it as “expired” so that it is then rapidly degraded by the ubiquitin-proteasome.
Discovering ACBI3
To get to this compound, the team, co-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 as possible of the oncogenic KRAS mutations by rationally designing degraders for them, instead of attempting to inhibit them, which is the most commonly used approach used for cancer targets.
Starting from high-quality small-molecule ‘prongs’ for KRAS at one end, linked to the E3 ligase von Hippel-Lindau (VHL) protein at the other end, they identified a first compound that was very promising at bringing the two proteins so close that they ‘sticked’ together, a featured often referred to as that of a ‘molecular glue’. This offered the team an attractive starting point for further investigation.
The team succeeded in co-crystalizing the three components KRAS, the PROTAC and VHL. Using X-ray crystallography they could visualize the structure of this complex down to atomic detail, helping them to 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 degrader step by step, in a rational and focused manner.
Joining forces with the global scientific community
Importantly, Boehringer Ingelheim plans to make the KRAS degrader compound ACBI3, freely available for the scientific community through its opnMe® portal, without any strings attached, which could catalyse future research on this important target.
opnMe® is the open science portal of Boehringer Ingelheim. It harnesses innovation by linking the best experts from across the globe with Boehringer scientists. opnMe® fosters independent scientific innovation with free, high-quality molecules for research purposes, research funding for new ideas on select molecules or scientific questions and PostDoc grants.
“Sharing this tool with the research community at large, will enable scientists to study the consequences and potential of degrading a key cancer-driving protein with the ultimate aim of transforming the lives of people living with cancer,” Dr. Ettmayer added.