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The 2013 paper from Kevan Shokat's laboratory that found a hidden pocket on one mutant form of KRAS and made small molecules that bind it, ending the belief that the protein could not be drugged.
Ostrem, Peters, Sos, Wells and Shokat report small molecules that bind irreversibly to the common oncogenic mutant K-Ras(G12C), relying on the mutant cysteine so that the wild-type protein is unaffected. Crystal structures reveal a new pocket, not apparent in earlier Ras structures, beneath the effector-binding switch-II region. Binding disrupts switch I and switch II, shifts the protein's nucleotide preference from GTP towards GDP and impairs binding to Raf. The authors describe this as structure-based validation of a new allosteric site on Ras that can be targeted in a mutant-specific manner, after decades in which the protein's picomolar nucleotide affinity and lack of known regulatory sites had defeated drug discovery.
Sotorasib and adagrasib (approved in lung cancer 2021 to 2022, active in the 1 to 2 percent of pancreatic cancers with G12C) descend from this chemistry; the non-covalent G12D inhibitors and the pan-RAS(ON) drugs that matter for pancreatic cancer came from the confidence it created.
Shares KRAS roadmap: undruggable → G12C → pan-RAS, Nature, KRAS & RAS inhibitors, The undruggable drivers and the tag pancreatic-evidence.
Shares CodeBreaK 100: sotorasib in KRAS p.G12C-mutated advanced pancreatic cancer, KRAS roadmap: undruggable → G12C → pan-RAS, KRAS & RAS inhibitors, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question and the tag pancreatic-evidence.
Shares Nature, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Nature, Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma, Non-small-cell lung cancer and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.
Shares Pancreatic cancer roadmap: from Whipple's operation to gemcitabine, FOLFIRINOX, adjuvant chemotherapy, PARP inhibition, KRAS inhibition, vaccines and the surveillance question, Pancreatic ductal adenocarcinoma and the tag pancreatic-evidence.