Ostrem and Shokat: the hidden pocket that made KRAS G12C druggable
Using disulfide-tethering screens, Shokat's laboratory found small molecules that bind covalently to the mutant cysteine of KRAS G12C in a previously unknown pocket beneath switch II, locking the oncoprotein in its inactive GDP-bound state.
KRAS had been considered undruggable for three decades because it binds GTP with picomolar affinity and has no obvious deep pocket. Ostrem and colleagues exploited the cysteine introduced by the G12C mutation, present in about 13% of lung adenocarcinomas, screening a library of cysteine-reactive fragments by tethering.
Crystal structures revealed that the hits bound in a cryptic pocket (switch-II pocket, S-IIP) that exists only in the GDP-bound state. The compounds impaired SOS-catalysed nucleotide exchange, shifted KRAS towards GDP binding, and reduced Raf effector binding, selectively killing G12C-mutant cells. The compounds were weak but demonstrated mechanism.
This work led directly to ARS-853, ARS-1620 and then sotorasib (approved 2021) and adagrasib (2022), the first KRAS inhibitors, and inspired covalent and non-covalent approaches to other RAS mutants.
- Identified covalent compounds binding cysteine 12 of KRAS G12C in a cryptic switch-II pocket visible only in the GDP-bound state
- Compounds impaired SOS-mediated nucleotide exchange and shifted the nucleotide preference from GTP to GDP
- Effector (Raf) binding was decreased and G12C-mutant cell viability selectively reduced
- Mutant-specific mechanism: wild-type KRAS was unaffected, giving a therapeutic window
The most frequently mutated oncogene in cancer stopped being undruggable, and patients with KRAS G12C lung and bowel cancers now have targeted pills. The approach, exploiting a mutation-created chemical handle and an inactive-state pocket, has become a template for other hard targets.
- The original compounds were micromolar tools, not drugs; a decade of medicinal chemistry was required
- Applies only to G12C; other KRAS mutants lack a reactive cysteine, though pan-RAS(ON) inhibitors are now emerging
- Clinical responses to G12C inhibitors are shorter than for EGFR or ALK inhibitors, and resistance is rapid
- Tumour-type dependence: colorectal G12C cancers respond poorly to monotherapy