F73: a RET inhibitor built to beat G810 solvent-front resistance
- Approved selective RET drugs lose effect when solvent-front G810C/R mutations emerge, so the authors ran a systematic SAR campaign starting from their earlier RET inhibitors.
- The resulting compound F73 stays potent against V804M gatekeeper and G810C/R variants, and blocks RET phosphorylation and downstream SHC signaling in mutant Ba/F3 cells.
- It triggers apoptosis and cell-cycle arrest dose-dependently in CCDC6-RET and G810R lines, and shows stronger antitumor activity than selpercatinib in a G810R xenograft.
💡 Points Based on the abstract
Gatekeeper and solvent-front mutations demand different answers: V804M is a steric clash that selpercatinib already sidesteps, whereas G810C/R crowds the hinge-exit region where the solvent-exposed tail sits. I'd want kinome selectivity next, since compounds tuned for mutants often regain off-target hits like KDR or FGFR. Also check whether activity holds in a G810 plus V804 compound-mutant background.