Synthetic approaches and clinical application of KRAS inhibitors for cancer therapy

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are among the most common oncogenic alterations in various cancers, including pancreatic, colorectal, and non-small cell lung cancer (NSCLC). Targeting KRAS has long been considered a difficult challenge due to its high affinity for guanosine triphosphate (GTP) and the lack of a druggable binding site. However, recent advancements in small-molecule inhibitor design have led to the development of targeted therapies aimed at KRAS mutations, particularly the KRAS^G12C mutation. Inhibitors such as Sotorasib and Adagrasib have shown promise in preclinical and clinical studies by irreversibly binding to the mutant KRAS protein, locking it in an inactive state and disrupting downstream signaling pathways critical for tumor growth and survival. These inhibitors have demonstrated clinical efficacy in treating patients with KRAS^G12C-mutated cancers, leading to tumor regression, prolonged progression-free survival, and improved patient outcomes. This review discusses the synthetic strategies employed to develop these KRAS inhibitor and also examines the clinical application of these inhibitors, highlighting the challenges and successes encountered during clinical trials. Ultimately, KRAS inhibitors represent a breakthrough in cancer therapy, offering a promising new treatment option for patients with KRAS-driven tumors.