UT Southwestern Medical Center cancer researchers have identified the SML-8-73-1 (SML) molecule as a selective and irreversible inhibitor of the mutated KRAS gene, an oncogene found in the majority of lung, colon and pancreatic cancers which renders patients less responsive to therapy.
The KRAS gene, or Kirsten rat sarcoma viral oncogene homolog, is responsible for the K-Ras protein that is directly involved in cellular proliferation. However, when this protein is mutated, uncontrolled cell division occurs, ultimately leading to the development of cancer.
Over the last 30 years, multiple attempts to develop a drug to inhibit K-Ras have failed. Dr. Kenneth Westover, Assistant Professor of Radiation Oncology and Biochemistry, member of UT Southwestern’s Harold C. Simmons Cancer Center and lead author of this study said “RAS proteins including KRAS have not been ‘druggable’ for many decades despite a lot of effort from academia and industry. We are exploring irreversible inhibitors as a solution, which we believe may pave the way for the development of KRAS-targeted compounds with therapeutic potential and perhaps compounds that target other RAS family proteins involved in cancer.”
The UT Southwestern team used high resolution X-ray crystallography to characterize the binding of SML to K-Ras carrying the G12C mutation, a characteristic mutation of tobacco-associated lung cancer and present in 25,000 of the new cases of lung cancer in the U.S. annually. The data revealed that the compound binds in a manner similar to its natural ligand guanosine diphosphate (GDP), forming a covalent linkage with the Cys-12 residue. This link results in the irreversible inactivation of K-Ras, which cannot associate productively with or activate its downstream effectors. Furthermore, high levels of GTP and GDP are not sufficient to knock off this connection and take its place instead.
Upon high-resolution in situ chemical proteomic profiling analysis, SML was confirmed to be highly selective, since it can effectively discriminate between K-Ras G12C and other cellular GTP-binding proteins that have similar configuration structures.
“We believe SML may be the first irreversible and selective inhibitor of KRAS,” said Dr. Westover, who was recruited to UT Southwestern with funds from the state-funded Cancer Research and Prevention Institute of Texas, and works both as a researcher, and as a clinician of the Lung Radiation Oncology Team at the Simmons Cancer Center. His laboratory has been particularly focused in the molecular biology of cancer, with the aim to develop potential anti-cancer therapies. In the future, Dr. Westover and his team intend to improve the SML compound to facilitate studies involving living cancer cells, eventually extending the research to animals and ultimately humans.
Other authors involved in this study, published in the Proceedings of the National Academy of Sciences and funded by the Cancer Research and Prevention Institute of Texas, and The Welch Foundation, include Dr. Zhe Chen, Assistant Professor of Biophysics, and postdoctoral researchers Dr. John Hunter, first author, Dr. Deepak Gurbani, and Dr. Martin Carrasco, in Radiation Oncology and Biochemistry.