Professor Kevan Shokat at UCSF has achieved a breakthrough in cancer drug discovery. The protein K-Ras has been described as “undruggable” for almost 40 years since its discovery as the first human oncogene in 1982. There has been a worldwide hunt for a drug to inhibit its role in cancer, but no drug was discovered because its structure lacked obvious drug-pockets. Shokat’s research team took an unconventional approach by focusing on one particular cancer causing variant, K-Ras (G12C).
The choice of a cysteine mutation allowed deployment of covalent bond formation of the drug to the target protein K-Ras (G12C). Using a drug screening approach based on sulfur-sulfur bond formation (disulfide tethering) his lab identified the first molecules to covalently attach to K-Ras (G12C). X-ray crystallography revealed a previously unknown pocket encompassing the drug. The protein molded around the drug once it was attached covalently to the protein thereby explaining why the pocket had been invisible in the previous decades. Once this pocket was visible and reported in 2013, multiple drug companies began racing to optimize the molecules for clinical trials. On May 28, 2021 the first drug targeting K-Ras (G12C) utilizing the pocket identified by Shokat was approved (sotorasib by Amgen). His work has catalyzed a resurgence in efforts to target K-Ras which is widely expected to produce a new category of targeted cancer therapies in lung, colon and pancreatic cancer.