Publication Showcases how First-to-Clinic Investigational AMG 510 Exploits a Cryptic Groove of the Previously Undruggable KRAS Protein SurfaceTHOUSAND OAKS, Calif., Oct. 30, 2019 — (PRNewswire) — Amgen (NASDAQ: AMGN) today announced a publication in Nature unveiling the discovery of AMG 510, a small molecule inhibitor of KRASG12C being investigated as a treatment for a variety of solid tumors with KRAS G12C mutation. AMG 510 is the first investigational KRASG12C inhibitor to advance to the clinic and is currently enrolling in a potentially registrational Phase 2 study.
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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 Amgen were the first to exploit the previously hidden groove on the protein surface to finally identify a potential drug against this important oncogenic protein," said David M. Reese, M.D., executive vice president of Research and Development at Amgen. "These scientific insights, coupled with superb molecular engineering, paved the way for AMG 510 to be first to clinic, where it has demonstrated early evidence of clinical activity."
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 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, Houston. "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."
The U.S. Food and Drug Administration (FDA) granted Orphan Drug Designation to AMG 510 for previously treated metastatic non-small cell lung cancer (NSCLC) and colorectal cancer with KRAS G12C mutation and Fast Track Designation for previously treated metastatic NSCLC with KRAS G12C mutation. Additional data from the ongoing Phase 1 clinical trial evaluating AMG 510 was recently presented at the 2019 World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer and at the European Society for Medical Oncology 2019 Congress, both of which were held in Barcelona, Spain.
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 the United States with KRAS G12C-driven cancers.4 KRASG12C has been considered "undruggable" due to a lack of traditional small molecule binding pockets on the protein. Amgen is exploring the potential of KRASG12C inhibition across a broad variety of tumor types.
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- 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.
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