Timeline of KRAS Inhibitors

After decades of efforts, scientists have made progress into targeting KRAS mutations in several malignancies. In 1967, Ha-Ras and Ki-Ras retroviral transforming genes were discovered. Their human counterparts, HRAS and KRAS, were discovered in 1982. The relationship between KRAS and lung cancer was described in 1984, KRAS mutation in lung cancer has progressed. Mutant KRAS is constitutively activated and leads to persistent downstream signaling and oncogenesis. In 2013, improved understanding of KRAS biology and newer drug designing technologies led to the crucial discovery of a cysteine drug-binding pocket in GDP-bound mutant KRAS G12C protein. In 2021, covalent inhibitors that block mutant KRAS G12C were successfully developed. In May 2021, the US FDA granted accelerated approval to Sotorasib for the treatment of adults with advanced NSCLC with a KRAS G12C mutation. Sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline. Lung adenocarcinoma often occurs in the distal gas exchange areas of the lung and is characterized by tumor cells with AT2 cytologic and molecular characteristics. Multiple studies have pointed out that AT2 cells are the key origin cells of LuAd. The stem cell activity of AT2 is selectively induced by epidermal growth factor receptor ligand (EGFR) and oncogenic KRAS (G12D) in vivo. KRAS (G12D) is induced in mice. G12D) followed by adenomatous tumor nodules. RAS is a family of GTPase proto-oncogenes, comprising three closely related RAS isoforms: HRAS, KRAS and NRAS. From all of the RAS isoforms, KRAS is most frequently mutated, followed by NRAS and then HRAS. KRAS mutations are particularly frequent in the pancreatic, lung and colorectal cancers. In cancer, the most frequently mutated residues are G12, G13, and Q61. KRAS protein exists as two splice variants, KRAS4A and KRAS4B, in which KRAS4B is the dominant form in human cells. In the formulation of KRAS integrated research plan, Medicilon has in-depth communication with customers. The backbone of scientific research has combined the characteristics of each case with years of practical experience and technical accumulation, and carefully submitted high-quality experimental plans and results to customers. Medicilon provides KRAS-targeted drug discovery, CMC research (API formulation), pharmacodynamics research, PK study, safety evaluation and other services.