Design, synthesis, and evaluation of aminopyrazolopyrimidopyridone derivatives as RETV804M and RETG810C inhibitors based on a "chemical adaptation" strategy.

Oncogenic conversion of the RET (rearranged during transfection) tyrosine kinase is a well-recognized drug target for cancer treatment. Despite the FDA approval of two selective second-generation RET inhibitors, selpercatinib and pralsetinib, acquired resistance through solvent-front mutations has been identified rapidly. RETG810 mutations at the solvent front site have been identified as the major on-target mutations contributing to resistance against selpercatinib and pralsetinib. Therefore, the development of next-generation RET inhibitors to overcome acquired solvent-front resistance mutations is urgently needed. In this study, a class of aminopyrazolpyrimidopyridone derivatives, such as RETV804M gatekeeper mutations and RETG810C solvent-front mutant inhibitors, were designed and synthesized to overcome resistance to second-generation RET inhibitors. One of the optimal compounds, 11ic, inhibited the proliferation of BaF3 cells harboring the CCDC6-RETV804M and CCDC6-RETG810C mutations, with IC50 values of 0.0208 μM and 0.096 μM, respectively. It presented a favorable oral pharmacokinetic profile, with an oral bioavailability of 26.9%, which exceeded that of our previously reported compound. Compound 11ic might be a promising lead compound for the development of novel RETV804M and RETG810C inhibitors to overcome clinical acquired resistance.