- ISOINDOLINE DERIVATIVES WHICH BIND TO AN ATP BINDING SITE
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The present invention relates to novel probe compounds of formulae I and II defined herein. The present invention also relates to methods of synthesising these novel probe compounds and to their use in assays and screens for determining the binding of a test molecule to the ATP-binding site of a target protein, such as, for example, the Mismatch Repair (MMR) component proteins PMS2 and MLH1, or for determining the location and/or quantity of such target proteins in a biological sample.
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Paragraph 00197-00198
(2021/07/31)
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- Effective synthesis of novel dihydrobenzisoxazoles bearing the 2-aminothiazole moiety and evaluation of the antiproliferative activity of their acylated derivatives
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An effective method for the synthesis of 8-aryl-4,5-dihydrothiazolo[4′,5′:3,4]benzo[1,2-c]isoxazol-2-amines was developed. This method includes the α-keto bromination of 3-aryl-6,7-dihydrobenzo[c]isoxazol-4(5H)-ones followed by the condensation of the obt
- Khlebnicova, Tatyana S.,Lakhvich, Fedor A.,Matous, Anton E.,Piven, Yuri A.,Scherbakov, Alexander M.,Shchegolev, Yuri Yu.,Sorokin, Danila V.,Yastrebova, Margarita A.,Zinovich, Veronica G.
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p. 10432 - 10443
(2021/12/17)
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- NOVEL COMPOUND HAVING HSP90 INHIBITORY ACTIVITY OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, AND MEDICAL USE THEREOF
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The present invention relates to a novel compound having HSP90 inhibitory activity or a pharmaceutically acceptable salt thereof, and a medicinal use thereof, and composition comprising a dihydroxyphenyl compound or a benzamide compound, which is a novel compound having the HSP90 inhibitory activity of the present invention can effectively inhibit HSP90, and thus can be usefully used as a pharmaceutical composition for preventing or treating HSP90-mediated diseases or a health functional food for preventing or improving HSP90-mediated diseases, which selected from the group consisting of cancer diseases, degenerative neurological diseases and viral infections.
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Paragraph 0190; 0191; 0192; 0193; 0194; 0290; 0291; 0292
(2019/02/13)
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- Design, synthesis and molecular mechanisms of novel dual inhibitors of heat shock protein 90/phosphoinositide 3-kinase alpha (Hsp90/PI3Kα) against cutaneous melanoma
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Overexpression of heat shock protein 90 (Hsp90) is common in various types of cancer. In cutaneous melanoma, a cancer with one of the high levels of Hsp90 overexpression, such expression was correlated with a panel of protein kinases, thus offering an opportunity to identify Hsp90-based multi-kinase inhibitors for novel cancer therapies. Towards this goal, we utilized a 2,4-dihydroxy-5-isopropylbenzate-based Hsp90 inhibitor scaffold and thieno[2,3-d]pyrimidine-based kinase inhibitor scaffold to develop a Hsp90-inhibiting compound library. Our inhibitory compound named 8m inhibited Hsp90 and PI3Kα with an IC50 value of 38.6 nM and 48.4 nM, respectively; it displayed improved cellular activity which could effectively induce cell cycle arrest and apoptosis in melanoma cells and lead to the inhibition of cell proliferation, colony formation, migration and invasion. Our results demonstrated 8m to be a promising lead compound for further therapeutic potential assessment of Hsp90/PI3Kα dual inhibitors in melanoma targeted therapy.
- Qin, Feifei,Wang, Yali,Jiang, Xian,Wang, Yujia,Zhang, Nan,Wen, Xiang,Wang, Lian,Jiang, Qinglin,He, Gu
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p. 909 - 926
(2019/04/13)
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- Design, synthesis, and biological evaluation of a series of resorcinol-based N-benzyl benzamide derivatives as potent Hsp90 inhibitors
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Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone that is responsible for the stabilization and maturation of many oncogenic proteins. Therefore, Hsp90 has emerged as an attractive target in the field of cancer chemotherapy. In this study, we report the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors. In particular, compound 30f shows a significant Hsp90α inhibitory activity with IC50 value of 5.3 nM and an excellent growth inhibition with GI50 value of 0.42 μM against non-small cell lung cancer cells, H1975. Compound 30f effectively reduces the expression levels of Hsp90 client proteins including Her2, EGFR, Met, Akt, and c-Raf. Consequently, compound 30f promotes substantial cleavages of PARP, Caspase 3, and Caspase 8, indicating that 30f induces cancer cell death via apoptotic pathway. Moreover, cytochrome P450 assay indicates that compound 30f has weak inhibitory effect on the activities of five major P450 isoforms (IC50 > 5 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between 30f and the substrate drugs of the five major P450 isoforms are not expected. Compound 30f also inhibits the tumor growth in a mouse xenograft model bearing subcutaneous H1975 without noticeable abnormal behavior and body weight changes. The immunostaining and western immunoblot analysis of EGFR, Met, Akt in xenograft tissue sections of tumor further demonstrate a good agreement with the in vitro results.
- Park, Sun You,Oh, Yong Jin,Lho, Yunmee,Jeong, Ju Hui,Liu, Kwang-Hyeon,Song, Jaeyoung,Kim, Soong-Hyun,Ha, Eunyoung,Seo, Young Ho
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p. 390 - 401
(2017/12/07)
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- Novel Compound and Anti-viral Composition Comprising the Same
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The present invention relates to a pharmaceutical composition and a feed additive, comprising a compound represented by chemical formula 2, a compound represented by chemical formula 1 or chemical formula 2, or a pharmaceutically acceptable salt thereof as an effective component. Specifically, compositions comprising the compound of the present invention as an effective component are safe to normal cells due to having no cytotoxicity, while effectively suppressing proliferation and transmission of disease-causing virus including porcine respiratory reproductive syndrome virus, and thus may be used as an agent for preventing or treating viral diseases.COPYRIGHT KIPO 2017
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Paragraph 0046; 0048; 0054; 0055
(2018/02/21)
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- Targeting the entry region of Hsp90's ATP binding pocket with a novel 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl amide
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The molecular chaperone Hsp90 plays an important role in cancer cell survival and proliferation by regulating the maturation and stabilization of numerous oncogenic proteins. Due to its potential to simultaneously disable multiple signaling pathways, Hsp90 has emerged as an attractive therapeutic target for cancer treatment. In this study, the design, synthesis, and biological evaluation of a series of Hsp90 inhibitors are described. Among the synthetic compounds, 6,7-dihydrothieno [3,2-c]pyridin-5(4H)-yl amide 19 exhibits a remarkable binding affinity to the N-terminus of Hsp90 in a fluorescence polarization (FP) binding assay (IC50= 50.3 nM). Furthermore, it effectively inhibits the proliferation of H1975 non-small cell lung cancer (NSCLC) and Skbr3 breast cancer cell lines with GI50values of 0.31 μM and 0.11 μM, respectively. Compound 19 induces the degradation of the Hsp90 client proteins including EGFR, Her2, Met, c-Raf, and Akt, and consequently promotes apoptotic cancer cell death. Compound 19 also inhibits the growth of H1975 xenografts in NOD-scid IL2R gammanullmice without any apparent body-weight loss. The immunohistologic evaluation indicates that compound 19 decreases the expression of Akt in xenograft tumor tissue via an inhibition of the Hsp90 chaperon function. Additionally, the cytochrome P450 assay indicates that compound 19 has no effect on the activities of five major P450 isoforms (IC50> 50 μM for 1A2, 2C9, 2C19, 2D6, and 3A), suggesting that clinical interactions between compound 19 and the substrate drugs of the five major P450 isoforms are not expected. Overall, compound 19 represents a new class of Hsp90 inhibitor with its 6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl-amide structure, and it has the therapeutic potential to overcome drug resistance in cancer chemotherapy.
- Jeong, Ju Hui,Oh, Yong Jin,Lho, Yunmee,Park, Sun You,Liu, Kwang-Hyeon,Ha, Eunyoung,Seo, Young Ho
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p. 1069 - 1080
(2016/11/09)
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- New thienopyridine compound having inhibitory activity on Hsp90 and medical use thereof
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The present invention relates to a novel thienopyridine compound having Hsp90 inhibitory activities, and relates to medical uses thereof. According to the present invention, the thienopyridine compound has excellent inhibitory effects of Hsp90, and induces the degradation of Hsp90 client protein, which generates cancer diseases or neurodegenerative diseases through the inhibition of Hsp90, thereby being efficiently used as a health food or a drug for treating or preventing Hsp90-mediated diseases such as cancer diseases or neurodegenerative diseases.COPYRIGHT KIPO 2016
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Paragraph 0043-0044; 0051-0055
(2017/04/12)
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- PHARMACEUTICAL COMPOUNDS
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The invention provides a compound of the formula (1 ): or a salt, solvate, N-oxide or tautomer thereof; wherein either R1 is R1a and R2 is R2a; or R1 is R1b and R2 is R2b; provided that in each case at least one of R1 and R2 is other than hydrogen; R1a and R2a are the same or different and each is selected from hydrogen, C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl wherein the C1-4 alkyl is optionally substituted by C1-2 alkoxy; R1b and R2b are the same or different and are selected from hydrogen, C(O)NR4R5, C(O)R6 and C(O)OR6 where R6 is C1-4 alkyl, R4 and R5 are both C1-4 alkyl, or NR4R5 forms a 4 to 7 membered saturated heterocyclic ring optionally containing a second heteroatom ring member selected from O, N or S and oxidised forms of N and S, the heterocyclic ring being optionally substituted by one or two C1-4 alkyl groups and/or one or two oxo groups; and R3 is a group (D): wherein the asterisk denotes the point of attachment to the isoindoline ring; but excluding acetic acid 5-acetoxy-4-isopropyl-2-[5-(4-methyl-piperazin-1 -ylmethyl)-1,3- dihydro-isoindole-2-carbonyl]-phenyl ester.
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Page/Page column 102
(2009/11/29)
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