Structure-Based Design of 2-Aminopyrazolpyrimidopyridone Derivatives as New Rearranged During Transfection (RET) Kinase Inhibitors.

RET (Rearranged during transfection) kinase is a validated target for non-small cell lung cancer (NSCLC). In 2020, two selective RET inhibitors, selpercatinib and pralsetinib were approved by the US FDA. However, high treatment costs and clinically acquired resistance (e.g., G810C/S/R) become the new challenges for RET-based therapies. In this work, we discovered a series of 2-aminopyrazolpyrimidopyridone RET inhibitors to overcome the V804M and G810C resistant mutations. One of the compounds, 8w, exhibited inhibitory potency against the BaF3 cells harboring CCDC6-RET^V804M mutation with an IC50 value of 0.715 μM. The compound also dose-dependently suppressed the activation of RET and downstream signals. Another compound, 8s suppressed BaF3 cells harboring CCDC6-RET^G810C mutation with an IC₅₀ value of 2.91 μM. However, the poor solubility of these compounds will limit their further development. Therefore, compound 8w and 8s might be promising lead compounds for the development of novel RET^V804M and RET^G810C inhibitors overcoming the clinically acquired resistance.