ARS-1620 and Neoplasms

Topics: Animals; Antineoplastic Agents; Guanosine Triphosphate; Humans; Mice; Mice, Nude; Mutation; Neoplasms; Proto-Oncogene Proteins p21(ras); Quinazolines

KRas is the most frequently mutated protein of the three Ras isoforms in various cancer types. KRas mutations (i.e. G12C) are present in approximately 30% of human cancers. Based on our previously reported KRas G12C inhibitor LLK-10, we designed a series of quinazoline analogues with a trifluoromethacrylic acid warhead as covalent inhibitor of KRas G12C. The pharmacological activities of these compounds were assessed against a panel of KRas G12C mutated cancer cells (i.e. H358 and H23). Among them, K20 showed that highest antiproliferative potency with an average IC

Topics: Animals; Guanosine Triphosphate; Humans; Mice; Mice, Nude; Mutation; Neoplasms; Piperazines; Proto-Oncogene Proteins p21(ras); Quinazolines

Although KRAS has been an important target for many cancers, direct inhibition of oncogenic RAS remains challenging. Until recently, covalent KRAS G12C-specific inhibitors have been developed and progressed to the clinics. Nevertheless, not all patients benefit from these covalent inhibitors. At present, identification of candidates for this treatment requires tissue biopsies and gene sequencing, which are invasive, time-consuming, and could be of insufficient quality and limited predictive value owing to tumor heterogeneity. The use of noninvasive molecular imaging techniques such as PET and SPECT for spying KRAS G12C mutation in tumors provide a promising strategy for circumventing these hurdles. In the present study, based on the covalent G12C-specific inhibitor ARS-1620, we sought to develop radiolabeled small molecules for direct imaging of the KRAS mutation status in tumors. [

Topics: Animals; Cell Line, Tumor; Female; Fluorine Radioisotopes; Humans; Iodine Radioisotopes; Mice; Molecular Docking Simulation; Molecular Imaging; Mutation; Neoplasms; Piperazines; Protein Kinase Inhibitors; Proto-Oncogene Proteins p21(ras); Quinazolines; Radiopharmaceuticals; Single Photon Emission Computed Tomography Computed Tomography; Tissue Distribution; Xenograft Model Antitumor Assays