A wounded oncogene
An invulnerable oncogene was found to have an Achilles heel for the first time
Copper News based on HHMI materials: Undruggable Mutation Meets Its MatchResearchers from the Howard Hughes Medical Institute (HHMI) at the University of California (San Francisco) for the first time managed to do what scientists in the world have not been able to do for the last 30 years: to identify a chemical compound - an inhibitor of the mutant oncogene K–Ras, most involved in malignant processes in humans and having a reputation in scientific circles as invulnerable to pharmacotherapy.
The work was published on November 20 in the journal Nature: Ostrem et al., K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions.
Ras are a family of proteins, the so-called small GTPases, and the genes encoding them. Ras are membrane-bound proteins that transmit signals between cells and play a central role in the regulation of cell proliferation. Mutations lead to permanent activation of Ras, uncontrolled cell division, tumor growth and metastasis. Somatic mutations in one of the Ras family genes, K-Ras, discovered about 30 years ago, are associated with about 30 percent of malignant neoplasms in humans, including 90 percent of cases of pancreatic cancer, 40 percent of cases of colon cancer, 20 percent of cases of non-small cell lung cancer. Oncological diseases associated with a mutation in the K-Ras gene have, as a rule, an aggressive course and do not respond well to standard therapies.
Until now, scientists have not been able to find the Achilles heel of the mutant K-Ras protein, which allows suppressing its activity, due to the inability to identify allosteric regulatory centers of the protein – sites of inhibitor binding. The group led by Kevan M. Shokat managed to do this due to the fact that the mutant variation of K-Ras was chosen as the object of the study, in which the amino acid glycine was replaced by the amino acid cysteine in the 12th position (G12C). Previously, researchers tried to work with other mutant versions of K-Ras, which did not bring results. The G12C mutation is the most common in K-Ras, it is responsible for seven percent of lung cancer cases.
Within three years, the Shokat group tested more than 500 low molecular weight chemical compounds for the ability to covalently bind to free cysteine in G12CK-Ras. As a result, a potential inhibitor was found, which was found to bind to a previously unknown allosteric site on the surface of the protein in the area of the cysteine group.
Illustration of the binding process of a chemical compound created by the Shokat group
with a site on the K-Ras surface
At the same time, the most important aspect of the discovery, which took a total of six years, Shokat stressed, is the fact that the found molecule blocks the activity of only the mutant, and not the normal K-Ras protein, due to a violation of its inherent biochemical mechanism.
The next step of the Shokat group, as indicated in the HHMI press release, will be to optimize the chemical compound they identified in order to test its effect on cancer cells with the G12C mutation. Johnson & Johnson's Janssen Biotech division, Shokat and his colleagues have already founded the biotech company Araxes Pharma, which, in partnership with Janssen Biotech, will prepare the K–Ras inhibitor for clinical use.
Portal "Eternal youth" http://vechnayamolodost.ru22.11.2013