- Discovery of a Pyrimidinedione Derivative as a Potent and Orally Bioavailable Axl Inhibitor
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The receptor tyrosine kinase Axl plays important roles in promoting cancer progression, metastasis, and drug resistance and has been identified as a promising target for anticancer therapeutics. We used molecular modeling-assisted structural optimization starting with the low micromolar potency compound 9 to discover compound 13c, a highly potent and orally bioavailable Axl inhibitor. Selectivity profiling showed that 13c could inhibit the well-known oncogenic kinase Met with equal potency to its inhibition of Axl superfamily kinases. Compound 13c significantly inhibited cellular Axl and Met signaling, suppressed Axl- and Met-driven cell proliferation, and restrained Gas6/Axl-mediated cancer cell migration or invasion. Furthermore, 13c exhibited significant antitumor efficacy in Axl-driven and Met-driven tumor xenograft models, causing tumor stasis or regression at well-tolerated doses. All these favorable data make 13c a promising therapeutic candidate for cancer treatment.
- Zhang, Hefeng,Peng, Xia,Dai, Yang,Shao, Jingwei,Ji, Yinchun,Sun, Yiming,Liu, Bo,Cheng, Xu,Ai, Jing,Duan, Wenhu
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supporting information
p. 3956 - 3975
(2021/04/12)
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- Rh(l)-catalyzed CO gas-free carbonylative cyclization reactions of alkynes with 2-bromophenylboronic acids using formaldehyde
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The rhodium(l)-catalyzed reaction of alkynes with 2-bromophenylboronic acids in the presence of paraformaldehyde resulted in a CO gas-free carbonylative cyclization, yielding indenone derivatives. [RhCI(BINAP)] 2 and [RhCI(cod)]2 wer
- Morimoto, Tsumoru,Yamasaki, Kae,Hirano, Akihisa,Tsutsumi, Ken,Kagawa, Natsuko,Kakiuchi, Kiyomi,Harada, Yasuyuki,Fukumoto, Yoshiya,Chatani, Naoto,Nishioka, Takanori
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supporting information; experimental part
p. 1776 - 1780
(2009/09/08)
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- Rh(I)-catalyzed carbonylative cyclization reactions of alkynes with 2-bromophenylboronic acids leading to indenones
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The Rh-catalyzed reaction of alkynes with 2-bromophenylboronic acids involves carbonylative cyclization to give indenones. The key steps in the reaction involve the addition of an arylrhodium(I) species to an alkyne and the oxidative addition of C-Br bond
- Harada, Yasuyuki,Nakanishi, Jun,Fujihara, Hirokazu,Tobisu, Mamoru,Fukumoto, Yoshiya,Chatani, Naoto
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p. 5766 - 5771
(2008/02/04)
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- DIFFERENTIATION MODULATING AGENTS AND USES THEREFOR
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This invention discloses methods and agents for modulating the differentiation potential and/or proliferation of preadipocytes. More particularly, the present invention discloses methods and agents for modulating a fibroblast growth factor (FGF) signalling pathway, especially the FGF-1 or FGF-2 signalling pathway, for treating or preventing adiposity-related conditions including, but not limited to, obesity, lipoma and lipomatosis.
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Page/Page column 182
(2010/02/12)
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- I-oxo-3-aryl-1H-indene-2-carboxylic acid derivatives as selective inhibitors of fibroblast growth factor receptor-1 tyrosine kinase
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Fibroblast growth factor receptor (FGFr) mediated signal transduction is implicated in vascular proliferative diseases and some cancers. We have identified methyl 1-oxo-3-phenyl-1H-indene-2-carboxylic ester as a small molecule inhibitor of the tyrosine ki
- Barvian,Panek,Lu,Kraker,Amar,Hartl,Hamby,Showalter
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p. 2903 - 2908
(2007/10/03)
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