The Discovery Of Amgen's Novel Investigational KRAS(G12C) Inhibitor AMG 510 Published In Nature
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Titled "The Clinical KRASG12C Inhibitor AMG 510 Drives Anti-Tumor Immunity," the paper highlights novel structural insights that led to the discovery of AMG 510, the preclinical evidence of AMG 510 activity, its potential ability to induce tumor-cell killing as both a monotherapy and in combination with other therapies, and its impact on the immune system that may render tumor cells particularly sensitive to immunotherapy. Early evidence of clinical activity of AMG 510 is also presented in the paper.
"We are pleased to share how our team of scientists at
KRAS, identified over 30 years ago as a proto-oncogene, is one of the most frequently mutated oncogenes in human cancer.1,2 Amgen researchers first identified the novel histidine 95 (H95) groove located on an inactive KRASG12C protein. Through extensive compound screening and structure-based design, AMG 510 emerged as the top investigational candidate from the optimization of a series of H95 groove-binding molecules. It is designed to irreversibly bind to KRASG12C protein and permanently lock it in an inactive state, leading to inhibition of tumor cell growth in KRASG12C driven tumors. In preclinical experiments, AMG 510 demonstrated favorable potency and selectivity, and induced regression in mice bearing KRASG12C mutated tumors.
"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," said
The subject of more than three decades of research, the RAS gene family are the most frequently mutated oncogenes in human cancers.1,2 Within this family, KRAS is the most prevalent variant and is particularly common in solid tumors.2 A specific mutation known as KRAS G12C accounts for approximately 13% of non-small cell lung cancers, three to five percent of colorectal cancers and one to two percent of numerous other solid tumors.3 Approximately 30,000 patients are diagnosed each year in
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The scientific information discussed in this news release related to
- Cox A, et al. Drugging the undruggable RAS: Mission possible? Nat Rev Drug Discov. 2014 Nov;13(11):828-51.
- Fernandez-Medarde A, Santos E. Ras in cancer and developmental diseases. Genes Cancer. 2011 Mar;2(3):344-58.
- Lipford, JR. Pre-clinical development of AMG 510: the first inhibitor of KRASG12C in clinical testing. Oral presentation at AACR 2019, Atlanta, GA.
March 29-April 3, 2019. Stephen AG, et al. Dragging ras back in the ring. Cancer Cell. 2014 Mar 17;25(3):272-81.