Sotorasiib belongs to the first generation of targeted drugs

Sotorasib (AMG510, Sotorasib) is a major breakthrough in the current field of precision cancer treatment and is known as the first approved KRAS G12C specific inhibitor. It is a small molecule targeted drug specifically used to treat patients with solid tumors with KRAS G12C mutations, especially in non-small cell lung cancer (NSCLC) and certain colorectal cancer subtypes. Although in the overall development history of targeted drugs, people often divide the "generations" of targeted drugs such as EGFR and ALK according to their targets and metabolic pathways, in the field of KRAS, sotorasibu is actually clearly defined as the first-generation KRAS G12C inhibitor, rather than the first, second or third-generation TKI in the traditional sense.

Unlike chemotherapy, immunotherapy or conventional tyrosine kinase inhibitors (TKI), the mechanism of action of sotorasibu does not rely on inhibition of kinase activity, but forms covalent and irreversible binding to the semi-active conformation of the KRAS G12C mutation site, thereby locking the mutant protein in an inactive state and blocking its downstream MAPK signaling pathway. This mechanism has never been successfully realized before, making KRAS, an "undruggable" target, truly enter the clinical treatment horizon for the first time, marking a new era of targeted tumor therapy. Therefore, in the KRAS mutation-targeted treatment sequence, sotorasiib is a representative drug among the first-generation products, laying the foundation for subsequent broader-spectrum, more potent or combined KRAS inhibitors.

Since KRAS G12C mutations are widely present in patients with NSCLC, pancreatic cancer, cholangiocarcinoma and some colorectal cancers. The successful launch of sotorasib not only opened the door to "customized" anti-KRAS treatment, but also spawned a variety of subsequent candidate drugs to enter clinical development, such as Adagrasib (MRTX849), which is classified as the first-generation KRAS G12C targeted drug camp.

Reference materials:https://www.lumakras.com/