- Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor
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The phosphoinositide 3-kinase (PI3K) family is one of the most frequently activated enzymes in a wide range of human cancers; thus, inhibition of PI3K represents a promising strategy for cancer therapy. Herein, a series of benzylamine substituted arylsulfonamides were designed and synthesized as dual PI3K/mTOR inhibitors using a strategy integrating focused library design and virtual screening, resulting in the discovery of 13b (NSC765844). The compound 13b exhibits highly potent enzyme inhibition with IC50s of 1.3, 1.8, 1.5, 3.8 and 3.8?nM for PI3Kα, β, γ, δ, and mTOR, respectively. 13b was further evaluated in NCI by an in?vitro cytotoxic screening program. Broad-spectrum antitumor activities with mean GI50value of 18.6?nM against approximately 60 human tumor cell lines were found. 13b displayed favorable physicochemical properties and superior pharmacokinetic profiles for animal studies. It significantly inhibited tumor growth when administered orally in an A549 non-small-cell lung carcinoma xenograft and BEL7404 human hepatocellular carcinoma xenograft models. On the basis of its excellent in?vivo efficacy and superior pharmacokinetic profiles, 13b has been selected for further preclinical investigation as a promising anticancer drug candidate.
- Han, Jinsong,Chen, Ying,Yang, Chao,Liu, Ting,Wang, Mingping,Xu, Haojie,Zhang, Ling,Zheng, Canhui,Song, Yunlong,Zhu, Ju
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p. 684 - 701
(2016/07/21)
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- Inhibitors of VEGF receptor and HGF receptor signaling
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The invention relates to the inhibition of VEGF receptor signaling and HGF receptor signaling. The invention provides compounds and methods for inhibiting VEGF receptor signaling and HGF receptor signaling. The invention also provides compositions and methods for treating cell proliferative diseases and conditions
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Page/Page column 85
(2010/11/25)
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- (HETERO)ARYL COMPOUNDS WITH MCH ANTAGONISTIC ACTIVITY AND MEDICAMENTS COMPRISING THESE COMPOUNDS
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The present invention relates to (hetero)aryl compounds of general formula (I) wherein the groups and radicals A, B, Q, W, X, Y, Z, R1, R2, R4a, R4b, R5a, R5b, have the meanings given in cl
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Page/Page column 77
(2010/11/27)
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