- HDAC DEGRADER
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The disclosure provides compounds of formula (I). The compounds may be used to degrade the Histone Deacetylase (HDAC) family of enzymes, particularly HDAC1, 2 and 3 that exist in corepressor complexes. Accordingly, the compounds may
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Page/Page column 41-42
(2021/07/31)
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- Design, synthesis and anticancer activities of novel dual poly(ADP-ribose) polymerase-1/histone deacetylase-1 inhibitors
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Currently, synergistic inhibition of poly(ADP-ribose) polymerase-1 (PARP-1) and histone deacetylases (HDACs) has been a potential effective strategy for cancer treatment. Herein, by combining critical pharmacophores in approved drugs olaparib and chidamid
- Liao, Chenzhong,Tian, Yongbin,Xie, Zhouling
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- Phthalazine derivative, preparation method and applications thereof
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The invention discloses a phthalazine derivative, a preparation method and applications thereof, and belongs to the field of medicinal chemistry, wherein the phthalazine derivative prepared by the invention is a good PARP and HDAC double-target inhibitor.
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- From methylene bridged diindole to carbonyl linked benzimidazoleindole: Development of potent and metabolically stable PCSK9 modulators
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a recently validated therapeutic target for lowering low-density lipoprotein cholesterol (LDL-C). Through phenotypic screening, we previously discovered a class of small-molecules with a 2,3′-diindolymethane (DIM) skeleton that can decrease the expression of PCSK9. But these compounds have low potency and low metabolically stability. After performing structure-activity relationship (SAR) optimization by nitrogen scan, deuterium substitution and fluorine scan, we identified a series of much more potent and metabolically stable PCSK9 modulators. A preliminary in vivo pharmacokinetic study was performed for representative analogues difluorodiindolyketone (DFDIK) 12 and difluorobenzoimidazolylindolylketone (DFBIIK-1) 13. The in vitro metabolic stability correlate well with the in vivo data. The most potent compound 21 has the EC50 of 0.15 nM. Our SAR studies also indicated that the NH on the indole ring of 21 can tolerate more function groups, which may facilitate the mechanism of action studies and also allow further improvement of the pharmacological properties.
- Xie, Haibo,Yang, Ka,Winston-McPherson, Gabrielle N.,Stapleton, Donnie S.,Keller, Mark P.,Attie, Alan D.,Smith, Kerry A.,Tang, Weiping
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- 1,3-dioxo-isoindoline benzamide compound and application thereof
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The invention belongs to the technical field of diabetes treatment medicines and in particular relates to an N-(2-aminophenyl)-3-(1,3-dioxo-isoindoline-2-yl) benzamide compound, and a preparation andapplication thereof in preparing diabetes treatment medicines. The compound has a formula (1) shown in the description, in the formula, R is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl, and X is selected from hydrogen or fluorine. The N-(2-aminophenyl)-3-(1,3-dioxo-isoindoline-2-yl) benzamide compound has a remarkable function of protecting pancreatic beta cells, and can be adopted to prepare novel diabetes treatment medicines.
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- HISTONE DEACETYLASE INHIBITORS
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Provided herein are compounds and methods for inhibiting histone deacetylase ("HDAC") enzymes (e.g., HDAC1, HDAC2, and HDAC3).
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- Design, synthesis and biological screening of 2-aminobenzamides as selective HDAC3 inhibitors with promising anticancer effects
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Histone deacetylases (HDACs) have been found as a potential target for anticancer therapy. A number of HDAC inhibitors have been used pre-clinically and clinically as anticancer agents. In the current study, we have designed and synthesized compound 12a by combining the scaffolds of CI-994 and BG45. Moreover, the structure of compound 12a was optimized and a series of 2-aminobenzamide derivatives were synthesized further. These compounds were tested for their HDAC inhibitory activity and found to be efficient HDAC inhibitors. Compound 26c showed 11.68-fold HDAC3 selectivity over pan HDACs, better than the prototype HDAC3 inhibitor BG45. Most of these compounds exhibited antiproliferative activity in both B16F10 and HeLa cell lines. Particularly, compound 26c exhibited better antitumor efficacy in the cell lines compared to the prototype inhibitors CI-994 and BG45. It was also found to promote apoptosis as well as induced significant cell growth arrest in the G2/M phase of cell cycle in B16F10 melanoma cells. This work may provide significant insight regarding structural information to design newer small molecule HDAC3 inhibitors to fight against the target specific malignancies in future.
- Trivedi, Prakruti,Adhikari, Nilanjan,Amin, Sk. Abdul,Jha, Tarun,Ghosh, Balaram
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p. 165 - 181
(2018/09/12)
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- HDAC3-SELECTIVE INHIBITORS
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Disclosed herein are selective HDAC inhibitors. In some embodiments, the compounds are selective HDAC3 inhibitors. The compounds are useful to treat a variety of conditions, including cancers, i.e., breast cancer, cachexia, and liver steatosis.
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- Selective HDAC inhibitors with potent oral activity against leukemia and colorectal cancer: Design, structure-activity relationship and anti-tumor activity study
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Previously, we reported the discovery of a series of N-hydroxycinnamamide-based HDAC inhibitors, among which compound 11y exhibited high HDAC1/3 selectivity. In this current study, structural derivatization of 11y led to a new series of benzamide based HDAC inhibitors. Most of the compounds exhibited high HDACs inhibitory potency. Compound 11a (with 4-methoxybenzoyl as N-substituent in the cap and 4-(aminomethyl) benzoyl as the linker group) exhibited selectivity against HDAC1 to some extent, and showed potent antiproliferative activity against several tumor cell lines. In?vivo studies revealed that compound 11a displayed potent oral antitumor activity in both hematological tumor cell U937 xenograft model and solid tumor cell HCT116 xenograft model with no obvious toxicity. Further modification of benzamide 3, 11a and 19 afforded new thienyl and phenyl compounds (50a, 50b, 63a, 63b and 63c) with dramatic HDAC1 and HDAC2 dual selectivity, and the fluorine containing compound 56, with moderate HDAC3 selectivity.
- Li, Xiaoyang,Zhang, Yingjie,Jiang, Yuqi,Wu, Jingde,Inks, Elizabeth S.,Chou, C. James,Gao, Shuai,Hou, Jinning,Ding, Qinge,Li, Jingyao,Wang, Xue,Huang, Yongxue,Xu, Wenfang
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p. 185 - 206
(2017/04/21)
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- Design, synthesis and anti-tumor activity study of novel histone deacetylase inhibitors containing isatin-based caps and o-phenylenediamine-based zinc binding groups
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As a hot topic of epigenetic studies, histone deacetylases (HDACs) are related to lots of diseases, especially cancer. Further researches indicated that different HDAC isoforms played various roles in a wide range of tumor types. Herein a novel series of HDAC inhibitors with isatin-based caps and o-phenylenediamine-based zinc binding groups have been designed and synthesized through scaffold hopping strategy. Among these compounds, the most potent compound 9n exhibited similar if not better HDAC inhibition and antiproliferative activities against multiple tumor cell lines compared with the positive control entinostat (MS-275). Additionally, compared with MS-275 (IC50 values for HDAC1, 2 and 3 were 0.163, 0.396 and 0.605?μM, respectively), compound 9n with IC50 values of 0.032, 0.256 and 0.311?μM for HDAC1, 2 and 3 respectively, showed a moderate HDAC1 selectivity.
- Gao, Shuai,Zang, Jie,Gao, Qianwen,Liang, Xuewu,Ding, Qinge,Li, Xiaoyang,Xu, Wenfang,Chou, C. James,Zhang, Yingjie
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p. 2981 - 2994
(2017/05/25)
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- Targeting breast cancer stem cells by novel HDAC3-selective inhibitors
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Although histone deacetylase (HDAC) inhibitors have been known to suppress the cancer stem cell (CSC) population in multiple types of cancer cells, it remains unclear which HDAC isoforms and corresponding mechanisms contribute to this anti-CSC activity. Pursuant to our previous finding that HDAC8 regulates CSCs in triple-negative breast cancer (TNBC) cells by targeting Notch1 stability, we investigated related pathways and found HDAC3 to be mechanistically linked to CSC homeostasis by increasing β-catenin expression through the Akt/GSK3β pathway. Accordingly, we used a pan-HDAC inhibitor, AR-42 (1), as a scaffold to develop HDAC3-selective inhibitors, obtaining the proof-of-concept with 18 and 28. These two derivatives exhibited high potency and isoform selectivity in HDAC3 inhibition. Equally important, they showed in vitro and/or in vivo efficacy in suppressing the CSC subpopulation of TNBC cells via the downregulation of β-catenin.
- Hsieh, Hao-Yu,Chuang, Hsiao-Ching,Shen, Fang-Hsiu,Detroja, Kinjal,Hsin, Ling-Wei,Chen, Ching-Shih
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- MACROCYCLIC HEPATITIS C SERINE PROTEASE INHIBITORS
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The present invention relates to novel macrocyclic compounds and methods of treating a hepatitis C infection in a subject in need of such therapy with said macrocyclic compounds. The present invention further relates to pharmaceutical compositions compris
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- (1H-Imidazo[4,5-c]pyridin-2-yl)-1,2,5-oxadiazol-3-ylamine derivatives: A novel class of potent MSK-1-inhibitors
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A novel series of imidazo[4,5-c]pyridines bearing a 1,2,5-oxadiazol-3- ylamine functionality has been developed. These are potent inhibitors of mitogen and stress-activated protein kinase-1.
- Bamford, Mark J.,Alberti, Michael J.,Bailey, Nicholas,Davies, Susannah,Dean, David K.,Gaiba, Alessandra,Garland, Stephen,Harling, John D.,Jung, David K.,Panchal, Terence A.,Parr, Christopher A.,Steadman, Jon G.,Takle, Andrew K.,Townsend, James T.,Wilson, David M.,Witherington, Jason
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p. 3402 - 3406
(2007/10/03)
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