Amgen’s AMG 510, the first therapy to reach clinical trials that inhibits a mutant KRAS protein, has demonstrated promising safety and efficacy results based on preliminary animal studies and clinical trials ongoing. It is now entering Phase II clinical trials. It got its start in a DOE-funded synchrotron facility at the University of California, Berkeley.
What is the significant of the KRAS gene?
Errors in the KRAS gene, which directs a critical cell signaling protein, represents one cause of cancer. One mutant called KRAS (G12C) is present in about 13% of lung adenocarcinomas, 3% of colorectal cancers and 2% of other solid tumors.
What is the drug AMG 510?
An investigational cancer drug made by Amgen that targets tumors caused by mutations in the KRAS gene. It is purportedly the first investigational KRAS therapy that inhibits a mutant KRAS protein.
Why hasn’t Researchers developed a candidate sooner?
Well as it turns out even though KRAS has a significant role in the pathogenesis of cancer, the shape of the underlying KRAS protein has made any design of a therapeutic challenging. Due to an extremely smooth surface there aren’t any regions, at least obvious ones, for a drug molecule to bind with—hence no easy approach to develop new drugs.
Enter UC Berkeley’s Advanced Light Source
Amgen, on a mission to find a direct inhibitor, contacted with UC Berkeley’s Advanced Light Source, a Department of Energy (DO) funded lab and conducted X-ray crystallography of KRAS (G12C) proteins. They produced high-resolution structural maps to help Amgen make the advanced discovery of a small pocket on the molecule; and in follow up studies they investigated at the atomic-level, molecular interactions between KRAS (G12C) and potential inhibiting compounds that bind in this newly identified pocket reported UC Berkeley Lab.
AMG 510 emerged from this advanced collaboration as a promising candidate after the multiyear drug agent optimization program.
UC Berkeley Advanced Light Source Comment
Marc Allaire, a biophysicist, operates the BCSB beamlines and noted “It’s rare that a compound gets all the way through the development process and becomes a drug. So, for the BCSB team, it feels great to see our (small) contribution finding its way to fight diseases.”
The Phase II Trial
The study seeks to evaluate the safety and tolerability of AMG 510 in adult subjects with KRAS p.G12c mutant advanced tumors. Study sponsor Amgen has recruited 51 study sites.