Development and Preclinical Evaluation of Radiolabeled Covalent G12C-Specific Inhibitors for Direct Imaging of the Oncogenic KRAS Mutant

• Published in: Molecular pharmaceutics 2021-09, Vol.18 (9), p.3509-3518
• Main Authors: Zhang, Zhe, Wang, Xiaobo, Ye, Jiajun, Liu, Huanhuan, Fang, Jianyang, Zhang, Mingru, Li, Yesen, Huang, Jinxiong, Zhang, Deliang, Wang, Jing, Zhang, Xianzhong
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Female; Fluorine Radioisotopes; Humans; Iodine Radioisotopes; Mice; Molecular Docking Simulation; Molecular Imaging - methods; Mutation; Neoplasms - diagnosis; Neoplasms - genetics; Piperazines - administration & dosage; Piperazines - pharmacokinetics; Protein Kinase Inhibitors - administration & dosage; Proto-Oncogene Proteins p21(ras) - antagonists & inhibitors; Quinazolines - administration & dosage; Quinazolines - pharmacokinetics; Radiopharmaceuticals - administration & dosage; Radiopharmaceuticals - pharmacokinetics; Single Photon Emission Computed Tomography Computed Tomography - methods; Tissue Distribution; Xenograft Model Antitumor Assays
• ISSN: 1543-8384; 1543-8392
• DOI: 10.1021/acs.molpharmaceut.1c00426

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. [131I]­I-ARS-1620 and [18F]­F-ARS-1620 were successfully prepared with high radiochemical yield, radiochemical purity, and molar activity. In vitro and in vivo studies have demonstrated the affinity, specificity, and capacity of [131I]­I-ARS-1620 for direct imaging of the oncogenic KRAS G12C mutant. This initial attempt allows us to directly screen the KRAS G12C mutant for the first time in vivo.