- Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer
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The development of inhibitors targeting the PI3K-Akt-mTOR signaling pathway has been greatly hindered by the on-target AEs, such as hyperglycemia and hepatotoxicities. In this study, a series of diaryl urea derivatives has been designed and synthesized based on clinical candidate gedatolisib (6aa), and most of the newly synthesized derivatives showed kinase inhibitory and antiproliferative activities within nanomolar and submicromolar level, respectively. The terminal l-prolineamide substituted derivative 6 ab showed 8.6-fold more potent PI3Kα inhibitory activity (0.7 nM) and 4.6-fold more potent antiproliferative effect against HCT116 cell lines (0.11 μM) compared with control 6aa. The potential antitumor mechanism and efficacy of 6 ab in HCT116 xenograft models have also been evaluated, and found 6 ab showed comparable in vivo antitumor activity with 6aa. The safety investigations revealed that compound 6 ab exhibited more safer profiles in the selectivity of liver cells (selectivity index: >6.6 vs 1.85) and blood glucose regulation than 6aa. In addition, the in vitro stability assays also indicated our developed compound 6 ab possessed good metabolic stabilities.
- Wu, Chun-Feng,Wang, Qing-Chen,Chen, Rui,Zhou, Hai-Ling,Wu, Ting-Ting,Du, Yao,Zhang, Na-Na,Zhang, Hui-Min,Fan, Zu-Yan,Wang, Li-Li,Hu, Chu-Jiao,Sang, Zhi-Pei,Li, Hong-Liang,Wang, Ling,Tang, Lei,Zhang, Ji-Quan
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- HSP90-TARGETING CONJUGATES AND FORMULATIONS THEREOF
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Conjugates of an active agent attached to a targeting moiety, such as an HSP90 binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
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- PI3Kalpha/mTOR bikinase inhibitor as well as pharmaceutical composition and application thereof
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The invention discloses a PI3Kalpha/mTOR bikinase inhibitor as well as a pharmaceutical composition and application thereof. The PI3Kalpha/mTOR bikinase inhibitor is prepared from a compound shown ina general formula (I), or a stereoisomer, a geometric isomeride, a hydrate, a solvate, or pharmaceutically acceptable salt or a prodrug: (the formula (1) is shown in the description.) The invention provides the PI3Kalpha/mTOR bikinase inhibitor and the pharmaceutical composition thereof for inhibiting PI3Kalpha/mTOR bikinase and proliferation diseases having a PI3Kalpha/mTOR bikinase effect; moreover, a more effective and higher selectivity inhibitor can be provided for treating the proliferation diseases having the PI3Kalpha/mTOR bikinase effect.
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- TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS
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Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.
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Paragraph 1059-1060
(2017/05/19)
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- Bis(morpholino-l,3,5-triazine) derivatives: Potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: Discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor
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The PI3K/Akt signaling pathway is a key pathway in cell proliferation, growth, survival, protein synthesis, and glucose metabolism. It has been recognized recently that inhibiting this pathway might provide a viable therapy for cancer. A series of bis(morpholino-1,3,5-triazine) derivatives were prepared and optimized to provide the highly efficacious PI3K/mTOR inhibitor 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4, 6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea 26 (PKI-587). Compound 26 has shown excellent activity in vitro and in vivo, with antitumor efficacy in both subcutaneous and orthotopic xenograft tumor models when administered intravenously. The structure-activity relationships and the in vitro and in vivo activity of analogues in this series are described.
- Venkatesan, Aranapakam M.,Dehnhardt, Christoph M.,Delos Santos, Efren D.,Chen, Zecheng,Dos Santos, Osvald D.,Ayral-Kaloustian, Semiramis,Khafizova, Gulnaz,Brooijmans, Natasja,Mallon, Robert,Hollander, Irwin,Feldberg, Larry,Lucas, Judy,Yu, Ker,Gibbons, James,Abraham, Robert T.,Chaudhary, Inder,Mansour, Tarek S.
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experimental part
p. 2636 - 2645
(2010/09/10)
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- PROCESS, PURIFICATION AND CRYSTALLIZATION OF 1-(4-{[4-(DIMETHYLAMINO)PIPERIDIN-1-YL]CARBONYL}PHENYL)-3-[4-(4,6-DIMORPHOLIN-4-YL-1,3,5-TRIAZIN-2-YL)PHENYL]UREA
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The invention relates to a method of making compounds of formula VII: (see formula) or a pharmaceutically acceptable salt thereof, wherein the constituent variables are as defined herein.
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Page/Page column 30
(2010/09/17)
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- TRIAZINE COMPOUNDS AS PI3 KINASE AND MTOR INHIBITORS
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Compounds of formula I wherein: R1 is and R2, R4, and R6-9 are defined herein, and pharmaceutically acceptable salts and esters thereof. These compounds inhibit PI3 kinase and mTOR, and may be used to treat diseases mediated by PI3 kinase and mTOR, such as a variety of cancers. Methods for making and using the compounds of this invention are disclosed. Various compositions containing the compounds of this invention are also disclosed.
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Page/Page column 44
(2009/12/05)
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