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The 2024 Nature paper describing the chemistry behind daraxonrasib: a reversible drug that clamps the active form of every RAS protein, mutant or normal, and shrank tumours across RAS-driven models.
Holderfield and colleagues at Revolution Medicines describe RMC-7977, a reversible tri-complex RAS inhibitor with broad-spectrum activity for the active (GTP-bound) state of mutant and wild-type KRAS, NRAS and HRAS, a RAS(ON) multi-selective inhibitor. Preclinically it showed potent activity against RAS-addicted tumours of various genotypes, particularly models with KRAS codon 12 mutations, led to tumour regression, was well tolerated in diverse models and inhibited KRAS G12C models that had become resistant to G12C inhibitors through restored RAS pathway signalling. The paper notes that KRAS G12C accounts for only around 15 percent of KRAS-mutant cancers and that no inhibitor was approved for the rest, and that the related compound RMC-6236 (daraxonrasib) was in clinical evaluation (NCT05379985).
The mechanism that let one drug address G12D, G12V and G12R together, which is why the RASolute 302 trial could enrol unselected pancreatic cancer and nearly double survival.
Shares KRAS roadmap: undruggable → G12C → pan-RAS, Nature, KRAS & RAS inhibitors, The undruggable drivers and the tag pancreatic-evidence.
Shares KRAS roadmap: undruggable → G12C → pan-RAS, The undruggable drivers, RAS / RAF / MEK / ERK (MAPK), 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, RAS / RAF / MEK / ERK (MAPK), 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 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 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 and the tag pancreatic-evidence.