151097-25-5Relevant articles and documents
ISOXAZOLE CARBOXAMIDE COMPOUNDS AND USES THEREOF
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, (2020/04/25)
A compound of Formula (I) or or a pharmaceutically acceptable salt thereof, is provided that has been shown to be useful for treating hearing loss or balance disorder: Formula (I) wherein R1 and Y are as defined herein.
Novel carboxamide-based allosteric MEK inhibitors: Discovery and optimization efforts toward XL518 (GDC-0973)
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
supporting information; experimental part, p. 416 - 421 (2012/06/30)
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 and have further demonstrated early evidence of efficacy in the clinic for the treatment of cancer. Guided by structural insight, a strategy aimed at the identification of an optimal diphenylamine-based MEK inhibitor with an improved metabolism and safety profile versus PD-0325901 led to the discovery of development candidate 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2S) -piperidin-2-yl]azetidin-3-ol (XL518, GDC-0973) (1). XL518 exhibits robust in vitro and in vivo potency and efficacy in preclinical models with sustained duration of action and is currently in early stage clinical trials.
METHODS OF USING COMBINATIONS OF MEK AND JAK-2 INHIBITORS
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Page/Page column 231-232, (2008/12/04)
A method of treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of a MEK compound of Formula I(M), or a pharmaceutical composition comprising a therapeutically effective amount of a MEK compound of Formula I(M) and a pharmaceutically acceptable carrier, in combination with a therapeutically effective amount of a JAK-2 compound of Formula I(J), or a pharmaceutical composition comprising a therapeutically effective amount of a JAK-2 compound of Formula I(J) and a pharmaceutically acceptable carrier, wherein the MEK compound of Formula I(M) and JAK-2 compound of Formula I(J) are as defined in the specification.