Cancer Drug Targeting Tumors Caused by the KRAS Gene Being Evaluated in Phase 2 Studies

Amgen says AMG 510 is the first investigational KRAS inhibitor to advance to the clinic for study
light at the end of the road

An investigational cancer drug that targets tumors caused by mutations in the KRAS gene will soon be evaluated in phase 2 clinical trials.

According to a December 23, 2019 press release, this drug, referred to as AMG 510, was developed by Amgen and currently is the first therapy to reach clinical trials that inhibits a mutant KRAS protein. 

This is potentially good news since errors in the KRAS gene, which encodes a crucial cell signaling protein, are one of the most common causes of cancer.

The particular mutant inhibited by AMG 510 – called KRAS(G12C) – is present in approximately 13 percent of lung adenocarcinomas, 3 percent of colorectal cancers, and 2 percent of other solid tumors.

Despite its significant role in the pathogenesis of cancer, scientists have been unable to design KRAS-specific therapeutics due to the shape of the protein – it has an exceptionally smooth surface with no obvious regions for a drug molecule to bind. 

Seeking to develop a long-sought direct inhibitor, researchers at Amgen conducted X-ray crystallography of KRAS(G12C) proteins at Berkeley Lab’s Advanced Light Source (ALS). 

The high-resolution structural maps generated using the data acquired at the beamlines helped Amgen make the breakthrough discovery of a small pocket on the molecule. 

In subsequent studies, the beamline data allowed scientists to investigate atomic-level molecular interactions between KRAS(G12C) and potential inhibiting compounds that bind in this pocket. 

AMG 510 emerged as a very promising candidate after a multiyear drug agent optimization program.

“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,” said Marc Allaire, one of the Berkeley Lab biophysicists who operate the BCSB beamlines, in this press release.

Previously, David S. Hong, M.D., one of the paper’s authors, AMG 510 clinical study investigator, and deputy chair, Department of Investigational Cancer Therapeutics, Division of Cancer Medicine at University of Texas MD Anderson Cancer Center, said: “There is a significant unmet need for tumor-selective therapies that minimize a negative impact on normal cells, and many patients diagnosed with KRAS-mutated solid tumors have typically faced a challenging prognosis with limited targeted treatment options.”

“This publication shows investigational AMG 510 has high selectivity in non-clinical experiments, binding only to KRASG12C out of more than 6,000 proteins and likely contributing to the absence of dose-limiting toxicities in the clinical study to date, supporting the potential for an encouraging safety profile,” concluded Dr. Hong on October 30, 2019.

Cancer news published by Vax Before Cancer