by A team of Center for Genomic Regulation in Barcelona and of Wellcome Sanger Institute in Cambridge (United Kingdom), has identified new therapeutic targets of the KRAS protein that can be very valuable for drug development, since they constitute secret vulnerabilities that can be used to control the effects of one of the most important causes of cancer. The study, which presents the first complete control map obtained so far for any protein, is published in the journal ‘Nature‘.
KRAS is one of the genes that suffers the most mutations in cancers of many types. It is found in one in ten human cancers, with a higher prevalence in severe types such as those of the pancreas or lung.
The KRAS oncogene is almost indestructible due to its spherical shape and the absence of areas where drugs could adhere to it. The protein to which it gives rise has been compared to the ‘star of death‘ from the ‘Star Wars’ universe due to its spherical shape and impenetrability, since it lacks a good place on its surface to be regulated with drugs. For this reason, KRAS has historically been considered ‘unapproachable’ since its discovery in 1982.
The only effective strategy to control KRAS has been to attack its allosteric communication system: molecular signals that operate through a lock and key ‘remote control’ mechanism. To control a protein, you need a chemical compound or drug that can open a lock (active site). Proteins can also be controlled by a secondary lock (allosteric site) located elsewhere on their surface.
However, the sites allosteric They are difficult to detect. After four decades of research, tens of miles of scientific publications, and more than three hundred published KRAS structures, only two drugs have been approved for clinical use: sotorasib and adagrasib. The drugs work by binding to a cavity adjacent to the active site, inducing an allosteric conformational change in the protein that prevents its activation.
“It took decades to produce an effective drug against KRAS, in part because we lacked tools to identify allosteric sites on a large scale, meaning we were blindly searching for therapeutic targets. In this study we demonstrate a new approach to map allosteric sites systematically in whole proteins. For the purposes of drug discovery, it’s like turning on the lights and exposing the many ways we can control a protein.», explains André Faure, scientist at the Center for Genomic Regulation and co-author of the study.
The study authors mapped allosteric sites and created more than 26,000 variations of the KRAS protein, changing only one or two amino acids at a time. The team checked how these different variations of KRAS bound to six other proteins, including those critical for KRAS to cause cancer.
The technique has shown that KRAS has many more sites than expected. Mutations at these sites inhibit interactions essential for KRAS function, suggesting that it is possible to broadly inhibit its activity. Some of these allosteric sites are very relevant, since they are found in four different cavities, each easily accessible on the surface of the protein, which is why they represent promising therapeutic targets for future drugs.
The authors of the study highlight one in particular, the ‘cavity 3′, as particularly interesting. This cavity is located far from the active site of KRAS and has therefore received very little attention from pharmaceutical companies.
