Discovery of F73, a New Generation RET Inhibitor Overcoming RET Gatekeeper (V804M) and Solvent-Front (G810C/R) Mutations

Abstract Pharmacological invention of RET offers a compelling strategy to treat patients harboring RET fusions or mutations. Selective RET inhibitors, including pralsetinib and selpercatinib, have demonstrated substantial clinical benefits. However, this efficacy is often compromised by the occurrence of resistance, particularly RET solvent front mutations G810C/R. To address this problem, we performed a systematic structure−activity optimization based on our reported RET inhibitors. Our efforts yielded F73, a next generation RET inhibitor with potent activity against RET mutations including V804M and G810C/R. F73 effectively suppressed RET phosphorylation and downstream SHC activation in Ba/Fa3 cells harboring various RET resistance mutations. Furthermore, it induced apoptosis and cell-cycle arrest in a dose-dependent manner in CCDC6-RET and CCDC6-RET-G810R Ba/F3 cells. Notably, F73 exhibited robust antitumor efficacy in Ba/F3-RET-G810R xenograft models, outperforming selpercatinib, thus supporting its potential to overcome resistance mediated by RET gatekeeper (V804M) and solvent-front (G810C/R) mutations.