- INHIBITORS OF THE MENIN-MLL INTERACTION
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The present invention is directed to inhibitors of the interaction of menin with MLL and MLL fusion proteins, pharmaceutical compositions containing the same, and their use in the treatment of cancer and other diseases mediated by the menin-MLL interaction.
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Page/Page column 118
(2017/07/14)
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- 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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- N-(5-(QUINOLIN-6-YL)PYRIDIN-3-YL) BENZSULFAMIDE DERIVATIVES, PREPARATION METHOD AND THERAPEUTIC USE THEREOF
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The present invention relates to the field of medical technology, and in particular, to a variety of substituted N-(5-(quinolin -6-yl)pyridin -3 -yl) bezsulfamide derivatives represented by formula (1) (groups therein are as defined in the specification).The compounds according to the present invention have favorable anti-tumor activity against human lung cancer, colon cancer, liver cancer, breast cancer and glioblastoma multiforme, which contribute to development of highly effective, low toxic and high specific anti-tumor drugs, and have high value of development. The present invention also relates to a composition, preparation method and use thereof in the preparation of anti-tumor drugs.
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Paragraph 0037
(2015/11/09)
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- Phospshoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitors: Discovery and structure-activity relationships of a series of quinoline and quinoxaline derivatives
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The phosphoinositide 3-kinase (PI3K) family catalyzes the ATP-dependent phosphorylation of the 3′-hydroxyl group of phosphatidylinositols and plays an important role in cell growth and survival. There is abundant evidence demonstrating that PI3K signaling is dysregulated in many human cancers, suggesting that therapeutics targeting the PI3K pathway may have utility for the treatment of cancer. Our efforts to identify potent, efficacious, and orally available PI3K/mammalian target of rapamycin (mTOR) dual inhibitors resulted in the discovery of a series of substituted quinolines and quinoxalines derivatives. In this report, we describe the structure-activity relationships, selectivity, and pharmacokinetic data of this series and illustrate the in vivo pharmacodynamic and efficacy data for a representative compound.
- Nishimura, Nobuko,Siegmund, Aaron,Liu, Longbin,Yang, Kevin,Bryan, Marian C.,Andrews, Kristin L.,Bo, Yunxin,Booker, Shon K.,Caenepeel, Sean,Freeman, Daniel,Liao, Hongyu,McCarter, John,Mullady, Erin L.,San Miguel, Tisha,Subramanian, Raju,Tamayo, Nuria,Wang, Ling,Whittington, Douglas A.,Zalameda, Leeanne,Zhang, Nancy,Hughes, Paul E.,Norman, Mark H.
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experimental part
p. 4735 - 4751
(2011/09/20)
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- INHIBITORS OF PI3 KINASE
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The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof; methods of treating diseases or conditions, such as cancer, using the compounds; and pharmaceutical compositions containing the compounds, wherein Q, X1, X2, R1 and Z are as defined herein.
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Page/Page column 90
(2010/01/12)
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