ABSTRACT
The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.
Subject(s)
Antineoplastic Agents , Lung Neoplasms , Neoplasms , Animals , Humans , Antineoplastic Agents/pharmacology , Proto-Oncogene Proteins p21(ras)/genetics , Neoplasms/drug therapy , Drug Design , Glycine/therapeutic use , Mutation , Lung Neoplasms/drug therapyABSTRACT
An operationally simple and efficient strategy for the synthesis of substituted tetrahydrofurans from readily available cis-butene-1,4-diol is described. A redox-relay Heck reaction is used to rapidly access cyclic hemiacetals that can be directly reduced to afford the corresponding 3-aryl tetrahydrofuran. Furthermore, the hemiacetals can also serve as precursors to a range of disubstituted tetrahydrofurans, including the calyxolane natural products.
