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排序方式: 共有1634条查询结果,搜索用时 31 毫秒
901.
902.
Peiyuan Zheng Jian Zhang Hui Ma Xinrui Yuan Pan Chen Jinpei Zhou Huibin Zhang 《Bioorganic & medicinal chemistry》2019,27(7):1391-1404
BRD9 is the subunit of mammalian SWI/SNF chromatin remodeling complex (BAF). SWI/SNF complex mutations were found in nearly 20% of human cancers. The biological role played by BRD9 bromodomain remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. In this paper, we synthesized a series of imidazo[1,5-a]pyrazin-8(7H)-one derivatives as potent BRD9 inhibitors and evaluated their BRD9 inhibitory activity in vitro and anti-proliferation effects against tumor cells. Gratifyingly, compound 27 and 29 exhibited robust potency of BRD9 inhibition with IC50 values of 35 and 103?nM respectively. Docking studies were performed to explain the structure-activity relationship. Furthermore, compound 27 potently inhibited cell proliferation in cell lines A549 and EOL-1 with an IC50 value of 6.12?μM and 1.76?μM respectively. The chemical probe, compound 27, was identified that should prove to be useful in further exploring BRD9 bromodomain biology in both in vitro and in vivo settings. 相似文献
903.
Yuka Miyake Yukihiro Itoh Atsushi Hatanaka Yoshinori Suzuma Miki Suzuki Hidehiko Kodama Yoshinobu Arai Takayoshi Suzuki 《Bioorganic & medicinal chemistry》2019,27(6):1119-1129
Histone lysine demethylases (KDMs) have drawn much attention as targets of therapeutic agents. KDM5 proteins, which are Fe(II)/α-ketoglutarate-dependent demethylases, are associated with oncogenesis and drug resistance in cancer cells, and KDM5-selective inhibitors are expected to be anticancer drugs. However, few cell-active KDM5 inhibitors have been reported and there is an obvious need to discover more. In this study, we pursued the identification of highly potent and cell-active KDM5-selective inhibitors. Based on the reported KDM5 inhibitors, we designed several compounds by strategically merging two fragments for competitive inhibition with α-ketoglutarate and for KDM5-selective inhibition. Among them, compounds 10 and 13, which have a 3-cyano pyrazolo[1,5-a]pyrimidin-7-one scaffold, exhibited strong KDM5-inhibitory activity and significant KDM5 selectivity. In cellular assays using human lung cancer cell line A549, 10 and 13 increased the levels of trimethylated lysine 4 on histone H3, which is a specific substrate of KDM5s, and induced growth inhibition of A549 cells. These results should provide a basis for the development of cell-active KDM5 inhibitors to highlight the validity of our inhibitor-based fragment merging strategy. 相似文献
904.
Yasunobu Yamashita Ken-ichiro Tanaka Naoki Yamakawa Teita Asano Yuki Kanda Ayaka Takafuji Masahiro Kawahara Mitsuko Takenaga Yoshifumi Fukunishi Tohru Mizushima 《Bioorganic & medicinal chemistry》2019,27(15):3339-3346
The treatment for patients with chronic obstructive pulmonary disease (COPD) usually involves a combination of anti-inflammatory and bronchodilatory drugs. We recently found that mepenzolate bromide (1) and its derivative, 3-(2-hydroxy-2, 2-diphenylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide (5), have both anti-inflammatory and bronchodilatory activities. We chemically modified 5 with a view to obtain derivatives with both anti-inflammatory and longer-lasting bronchodilatory activities. Among the synthesized compounds, (R)-(–)-12 ((R)-3-(2-hydroxy-2,2-diphenylacetoxy)-1-(3-phenylpropyl)-1-azoniabicyclo[2.2.2]octane bromide) showed the highest affinity in vitro for the human muscarinic M3 receptor (hM3R). Compared to 1 and 5, (R)-(–)-12 exhibited longer-lasting bronchodilatory activity and equivalent anti-inflammatory effect in mice. The long-term intratracheal administration of (R)-(–)-12 suppressed porcine pancreatic elastase-induced pulmonary emphysema in mice, whereas the same procedure with a long-acting muscarinic antagonist used clinically (tiotropium bromide) did not. These results suggest that (R)-(–)-12 might be therapeutically beneficial for use with COPD patients given the improved effects seen against both inflammatory pulmonary emphysema and airflow limitation in this animal model. 相似文献
905.
906.
Raushan K. Singh Kyongshin Cho Satish K. R. Padi Junru Yu Manas Haldar Tanmay Mandal Changhui Yan Gregory Cook Bin Guo Sanku Mallik D. K. Srivastava 《The Journal of biological chemistry》2015,290(10):6607-6619
We reported previously that an N-acylthiourea derivative (TM-2-51) serves as a potent and isozyme-selective activator for human histone deacetylase 8 (HDAC8). To probe the molecular mechanism of the enzyme activation, we performed a detailed account of the steady-state kinetics, thermodynamics, molecular modeling, and cell biology studies. The steady-state kinetic data revealed that TM-2-51 binds to HDAC8 at two sites in a positive cooperative manner. Isothermal titration calorimetric and molecular modeling data conformed to the two-site binding model of the enzyme-activator complex. We evaluated the efficacy of TM-2-51 on SH-SY5Y and BE(2)-C neuroblastoma cells, wherein the HDAC8 expression has been correlated with cellular malignancy. Whereas TM-2-51 selectively induced cell growth inhibition and apoptosis in SH-SY5Y cells, it showed no such effects in BE(2)-C cells, and this discriminatory feature appears to be encoded in the p53 genotype of the above cells. Our mechanistic and cellular studies on HDAC8 activation have the potential to provide insight into the development of novel anticancer drugs. 相似文献
907.
908.
Rangasudhagar Radhakrishnan Yixuan Li Shengyan Xiang Fenghua Yuan Zhigang Yuan Elphine Telles Jia Fang Domenico Coppola David Shibata William S. Lane Yanbin Zhang Xiaohong Zhang Edward Seto 《The Journal of biological chemistry》2015,290(37):22795-22804
MutS homolog 2 (MSH2) is an essential DNA mismatch repair (MMR) protein. It interacts with MSH6 or MSH3 to form the MutSα or MutSβ complex, respectively, which recognize base-base mispairs and insertions/deletions and initiate the repair process. Mutation or dysregulation of MSH2 causes genomic instability that can lead to cancer. MSH2 is acetylated at its C terminus, and histone deacetylase (HDAC6) deacetylates MSH2. However, whether other regions of MSH2 can be acetylated and whether other histone deacetylases (HDACs) and histone acetyltransferases (HATs) are involved in MSH2 deacetylation/acetylation is unknown. Here, we report that MSH2 can be acetylated at Lys-73 near the N terminus. Lys-73 is highly conserved across many species. Although several Class I and II HDACs interact with MSH2, HDAC10 is the major enzyme that deacetylates MSH2 at Lys-73. Histone acetyltransferase HBO1 might acetylate this residue. HDAC10 overexpression in HeLa cells stimulates cellular DNA MMR activity, whereas HDAC10 knockdown decreases DNA MMR activity. Thus, our study identifies an HDAC10-mediated regulatory mechanism controlling the DNA mismatch repair function of MSH2. 相似文献
909.
910.