Novel carboxamide-based allosteric MEK inhibitors: discovery and optimization efforts toward XL518 (GDC-0973)

…, OJ Bowles, J Bussenius, S Costanzo…

文献索引：Rice, Kenneth D.; Aay, Naing; Anand, Neel K.; Blazey, Charles M.; Bowles, Owen J.; Bussenius, Joerg; Costanzo, Simona; Curtis, Jeffry K.; Defina, Steven C.; Dubenko, Larisa; Engst, Stefan; Joshi, Anagha A.; Kennedy, Abigail R.; Kim, Angie I.; Koltun, Elena S.; Lougheed, Julie C.; Manalo, Jean-Claire L.; Martini, Jean-Francois; Nuss, John M.; Peto, Csaba J.; Tsang, Tsze H.; Yu, Peiwen; Johnston, Stuart ACS Medicinal Chemistry Letters, 2012 , vol. 3, # 5 p. 416 - 421

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被引用次数: 34

摘要

The ERK/MAP kinase cascade is a key mechanism subject to dysregulation in cancer and is constitutively activated or highly upregulated in many tumor types. Mutations associated with upstream pathway components RAS and Raf occur frequently and contribute to the oncogenic phenotype through activation of MEK and then ERK. Inhibitors of MEK have been shown to effectively block upregulated ERK/MAPK signaling in a range of cancer cell lines ...