119293-22-0Relevant academic research and scientific papers
Bcl-2/Bcl-xL inhibition increases the efficacy of MEK inhibition alone and in combination with PI3 kinase inhibition in lung and pancreatic tumor models
Tan, Nguyen,Wong, Maureen,Nannini, Michelle A.,Hong, Rebecca,Lee, Leslie B.,Price, Stephen,Williams, Karen,Savy, Pierre Pascal,Yue, Peng,Sampath, Deepak,Settleman, Jeffrey,Fairbrother, Wayne J.,Belmont, Lisa D.
, p. 853 - 864 (2013/07/26)
Although mitogen-activated protein (MAP)-extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition is predicted to cause cell death by stabilization of the proapoptotic BH3-only protein BIM, the induction of apoptosis is often modest. To determine if addition of a Bcl-2 family inhibitor could increase the efficacy of a MEK inhibitor, we evaluated a panel of 53 non-small cell lung cancer and pancreatic cancer cell lines with the combination of navitoclax (ABT-263), a Bcl-2/Bcl-xL (BCL2/BCL2L1) antagonist, and a novel MAP kinase (MEK) inhibitor, G-963. The combination is synergistic in the majority of lines, with an enrichment of cell lines harboring KRAS mutations in the high synergy group. Cells exposed to G-963 arrest in G1 and a small fraction undergo apoptosis. The addition of navitoclax to G-963 does not alter the kinetics of cell-cycle arrest, but greatly increases the percentage of cells that undergo apoptosis. The G-963/navitoclax combination was more effective than either single agent in the KRAS mutant H2122 xenograft model; BIM stabilization and PARP cleavage were observed in tumors, consistent with the mechanism of action observed in cell culture. Addition of the phosphatidylinositol 3-kinase (PI3K, PIK3CA) inhibitor GDC-0941 to this treatment combination increases cell killing compared with double- or single-agent treatment. Taken together, these data suggest the efficacy of agents that target the MAPK and PI3K pathways can be improved by combination with a Bcl-2 family inhibitor.
AZA-BENZOFURANYL COMPOUNDS AND METHODS OF USE
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Page/Page column 65-66, (2008/06/13)
The invention relates to azabenzofuranyl compounds of Formula (I) with anti-cancer and/or anti-inflammatory activity and more specifically to azabenzofuranyl compounds which inhibit MEK kinase activity. The invention provides compositions and methods useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder, or treating an inflammatory disease in a mammal. The invention also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.
SPIROFUROPYRIDINE ARYL DERIVATIVES
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Page/Page column 16; 17, (2008/06/13)
Compounds of formula (I): and pharmaceutically-acceptable salts thereof, wherein: Ar is a moiety of formula (II) or (III): and A, B, and R1 are as defined in the specification, compositions containing such compounds and the use of such compounds and compositions for use in therapy.
Furopyridines. IX . Syntheses and Properties of 3-Ethoxy Derivatives of Furo-, Furo-, Furo- and Furopyridine
Shiotani, Shunsaku,Morita, Hiroyuki,Ishida, Toshimasa,In, Yasuko
, p. 1205 - 1213 (2007/10/02)
Reaction of ethyl 3-ethoxycarbonylmethoxyfuropyridine-2-carboxylates 2a-2d with sodium ethoxide afforded 3-ethoxy derivatives 3a-3d which converted to 3-ethoxyfuropyridines 5a-5d by hydrolysis and decarboxylation of the ester group.Vilsmeier reaction of 5a and 5b gave 2-formyl-3-ethoxy derivatives 6a and 6b and 2-formyl-3-chloro derivatives 7a and 7b, while 5c and 5d did not give any formyl compound.Bromination of 3-ethoxyfuropyridines with 1 equivalent mole of bromine gave 2-bromo-3-ethoxyfuropyridines 9a-9d, whereas reaction with 3 equivalents of bromine yielded 2,2- dibromo-3,3-diethoxy-2,3-dihydrofuropyridines (10a and 10b) and/or 2-bromo-3,3-diethoxy-2,3-dihydrofuropyridines 11b, 11c and 11d.Treatment of compounds 5a-5d with n-butyllithium in hexane-tetrahydrofuran at -70 deg C and subsequent addition of N,N-dimethylformamide yielded 2-formyl derivatives 6a-6d.
