- Design, synthesis and biological evaluation of novel hybrids targeting mTOR and HDACs for potential treatment of hepatocellular carcinoma
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Hepatocellular carcinoma (HCC) is a major contributor to global cancer incidence and mortality. Many pathways are involved in the development of HCC and various proteins including mTOR and HDACs have been identified as potential drug targets for HCC treatment. In the present study, two series of novel hybrid molecules targeting mTOR and HDACs were designed and synthesized based on parent inhibitors (MLN0128 and PP121 for mTOR, SAHA for HDACs) by using a fusion-type molecular hybridization strategy. In vitro antiproliferative assays demonstrated that these novel hybrids with suitable linker lengths exhibited broad cytotoxicity against various cancer cell lines, with significant activity against HepG2 cells. Notably, DI06, an MLN0128-based hybrid, exhibited antiproliferative activity against HepG2 cells with an IC50 value of 1.61 μM, which was comparable to those of both parent drugs (MLN0128, IC50 = 2.13 μM and SAHA, IC50 = 2.26 μM). In vitro enzyme inhibition assays indicated that DI06, DI07 and DI17 (PP121-based hybrid) exhibited nanomolar inhibitory activity against mTOR kinase and HDACs (e.g., HDAC1, HDAC2, HDAC3, HADC6 and HADC8). Cellular studies and western blot analyses uncovered that in HepG2 cells, DI06 and DI17 induced cell apoptosis by targeting mTOR and HDACs, blocked the cell cycle at the G0/G1 phase and suppressed cell migration. The potential binding modes of the hybrids (DI06 and DI17) with mTOR and HDACs were investigated by molecular docking. DI06 displayed better stability in rat liver microsomes than DI07 and DI17. Collectively, DI06 as a novel mTOR and HDACs inhibitor presented here warrants further investigation as a potential treatment of HCC.
- Zhai, Shiyang,Zhang, Huimin,Chen, Rui,Wu, Jiangxia,Ai, Daiqiao,Tao, Shunming,Cai, Yike,Zhang, Ji-Quan,Wang, Ling
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- PI3Kalpha selective inhibitor and preparation method and application thereof
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The invention discloses a PI3Kalpha selective inhibitor and a preparation method and application thereof, a triazine ring benzoxazole compound and a preparation method and application thereof, and the structural formula of the compound is shown as a formula I or a pharmaceutically acceptable salt thereof. Biochemical activity tests show that the compounds have good inhibitory activity on PI3K alpha, so that the compounds can provide effective inhibitors with better selectivity for treatment of diseases regulated by PI3K, and target drugs for treating diseases related to PI3K signal pathways, such as gastric cancer, breast cancer, ovarian cancer and leukemia, are expected to be developed.
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Paragraph 0078-0080
(2021/08/06)
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- 5 - Pyridyl -2 - amino - benzo [d] oxazole derivative and its preparation and use (by machine translation)
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The present invention discloses the general formula (I) indicated by the 5 - pyridyl - 2 - amino - benzo [d] oxazole derivative or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and use: According to the compounds of this invention can be used for preparing the treatment of cervical cancer, breast cancer, stomach cancer, liver cancer, renal carcinomas of the drug. (by machine translation)
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- TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS OF USE
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Described herein are tricyclic compounds with phosphoinositide-3 kinase (PI3K) modulation activity or function having the Formula I structure: or stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, and with the substituents and structural features described herein. Also described are pharmaceutical compositions and medicaments that include the Formula I compounds, as well as methods of using such PI3K modulators, alone and in combination with other therapeutic agents, for treating diseases or conditions that are mediated or dependent upon PI3K dysregulation.
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- METALLO-BETA-LACTAMASE INHIBITORS
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The present invention relates to compounds of formula I that are metallo-β-lactamase inhibitors, the synthesis of such compounds, and the use of such compounds for use with β-lactam antibiotics for overcoming resistance.
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Page/Page column 76; 77
(2017/04/04)
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- Enhanced treatment regimens using mTor inhibitors
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The present invention provides for methods and pharmaceutical compositions comprising inhibitors of mTorC1 and/or mTorC2. In some aspects, the invention provides for treatment regimens resulting in enhanced treatment efficacy and better tolerability.
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- COMBINATION OF KINASE INHIBITORS AND USES THEREOF
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The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase α and/or mTOR in a subject.
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- COMBINATION PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
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The present invention provides for methods and pharmaceutical compositions for treating proliferative disorders. In one aspect, the method comprises administration of two cell-cycle suppressors having a synergistic effect. In another aspect, two cell-cycle suppressors having a synergistic effect are provided in a pharmaceutical composition.
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- KINASE INHIBITOR POLYMORPHS
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Polymorphs of chemical compounds that modulate kinase activity, including PI3K activity, and chemical compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including PI3K activity, are described herein.
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- KINASE INHIBITOR POLYMORPHS
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Polymorphs, hydrates, and solvates of chemical compounds that modulate kinase activity, including mTOR activity, and chemical compounds, pharmaceutical compositions, and methods of treatment of diseases and conditions associated with kinase activity, including mTOR activity, are described herein.
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- BENZOXAZOLE KINASE INHIBITORS AND METHODS OF USE
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The present invention provides chemical entities or compounds and pharmaceutical compositions thereof that are capable of modulating certain protein kinases such as mTor, tyrosine kinases, and/or lipid kinases such as PI3 kinase. Also provided in the present invention are methods of using these compositions to modulate activities of one or more of these kinases, especially for therapeutic applications.
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Page/Page column 27; 133; 219
(2010/05/14)
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