Zoldonrasib: an oral covalent tri-complex inhibitor of active KRAS G12D
- Structure-guided SAR optimization produced zoldonrasib, an orally available tri-complex inhibitor that selectively targets the GTP-bound, active form of KRAS G12D.
- An aziridine-2-carboxamide warhead and a rigid spirocyclic linker were key to selective covalent engagement of the mutant protein.
- The compound suppressed KRAS G12D signaling in dependent cells, showed good ADME and pharmacokinetics across species, and drove tumor regressions in xenograft models; it is now in clinical evaluation.
💡 Points Based on the abstract
An aziridine on a G12D-directed ligand is a bold choice: unlike G12C cysteine chemistry, it has to find an aspartate carboxylate, so intrinsic reactivity is a selectivity risk. I'd want proteome-wide reactivity profiling and wild-type RAS occupancy data, plus GSH and plasma stability. Does the rigid spiro linker mostly pre-organize the warhead, or buy oral exposure?