Discovery of AZD4747, a Potent and Selective Inhibitor of Mutant GTPase KRASG12C with Demonstrable CNS Penetration
JOURNAL OF MEDICINAL CHEMISTRY(2023)
摘要
Theglycine to cysteine mutation at codon 12 of Kirstenrat sarcoma(KRAS) represents an Achilles heel that has now rendered this importantGTPase druggable. Herein, we report our structure-based drug designapproach that led to the identification of 14, AZD4747,a clinical development candidate for the treatment of KRAS(G12C)-positive tumors, including the treatment of central nervous system(CNS) metastases. Building on our earlier discovery of C5-tetheredquinazoline AZD4625, excision of a usually critical pyrimidine ringyielded a weak but brain-penetrant start point which was optimizedfor potency and DMPK. Key design principles and measured parametersthat give high confidence in CNS exposure are discussed. During optimization,divergence between rodent and non-rodent species was observed in CNSexposure, with primate PET studies ultimately giving high confidencein the expected translation to patients. AZD4747 is a highly potentand selective inhibitor of KRAS(G12C) with an anticipatedlow clearance and high oral bioavailability profile in humans.
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关键词
mutant gtpase kras<sup>g12c</sup>,selective inhibitor,azd4747
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