- Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization
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PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.
- Mao, Ruifeng,Shao, Jingwei,Zhu, Kongkai,Zhang, Yuanyuan,Ding, Hong,Zhang, Chenhua,Shi, Zhe,Jiang, Hualiang,Sun, Dequn,Duan, Wenhu,Luo, Cheng
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p. 6289 - 6304
(2017/08/02)
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- Imidazopyridine- and purine-thioacetamide derivatives: Potent inhibitors of nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1)
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Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) belongs to the family of ecto-nucleotidases, which control extracellular nucleotide, nucleoside, and (di)phosphate levels. To study the (patho)physiological roles of NPP1 potent and selective inhibitors with drug-like properties are required. Therefore, a compound library was screened for NPP1 inhibitors using a colorimetric assay with p-nitrophenyl 5′-thymidine monophosphate (p-Nph-5′-TMP) as an artificial substrate. This led to the discovery of 2-(3H-imidazo[4,5-b]pyridin-2-ylthio)-N-(3,4-dimethoxyphenyl)acetamide (5a) as a hit compound with a Ki value of 217 nM. Subsequent structure-activity relationship studies led to the development of purine and imidazo[4,5-b]pyridine analogues with high inhibitory potency (Ki values of 5.00 nM and 29.6 nM, respectively) when assayed with p-Nph-5′-TMP as a substrate. Surprisingly, the compounds were significantly less potent when tested versus ATP as a substrate, with Ki values in the low micromolar range. A prototypic inhibitor was investigated for its mechanism of inhibition and found to be competitive versus both substrates.
- Chang, Lei,Lee, Sang-Yong,Leonczak, Piotr,Rozenski, Jef,De Jonghe, Steven,Hanck, Theodor,Müller, Christa E.,Herdewijn, Piet
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p. 10080 - 10100
(2015/02/05)
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- FUSED HETEROCYCLIC COMPOUNDS
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The present invention provides a compound which has the effect of PDE inhibition, and which is useful as an agent for preventing or treating schizophrenia. The compound is represented by the formula (I): wherein the symbols are defined in the specification.
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Page/Page column 88
(2012/01/13)
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- Imidazo(4,5-C)pyridines as antiosteoporotic agents
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This invention relates to 2-substituted-imidazo[4,5-c]pyridines, to the process for their preparation, to pharmaceutical compositions containing said 2-substituted-imidazo[4,5-c]pyridines and to the use of said 2-substituted-imidazo[4,5-c]pyridines for mo
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- Production of certain 2-phenylalkylthio-and 2-phenylalkylsulfinyl imidazo[4,]pyridines
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This invention relates to the process for the preparation of certain 2-phenylalkylthio- and phenylalkylsulfinyl-imidazo[4,5-c]pyridines useful for the treatment of osteoporosis.
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- THIONATION OF IMIDAZOPYRIDINES
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Direct thionation of imidazopyridines and imidazopyridines results in the formation of their 2-thioxo derivatives, usually in high yield.The thione structure of the imidazopyridines obtained has been confirmed from their IR spectra in the solid state and in solution.The general nature of the thionation of imidazole, benzimidazole, imidazopyridine, imidazopyridine, and purine has been noted as one of the distinctive chemical properties of compounds in this series of nitrogen heterocycles.
- Yutilov, Yu.M.,Svertilova, I.A.
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p. 653 - 658
(2007/10/02)
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- A Facile Synthesis of 8-Arylamino- and 8-Hetarylaminopurines and their 1- and 3-Deaza Analogs
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A general method for the synthesis of 8-arylamino- and 8-(2-benzothiazolylamino)-purines and their 1- and 3-deaza analogs is reported.The need for the presence of the desulfurizing agent in the preparation of the 8-arylamino derivatives is demonstrated an
- Garin, J.,Melendez, E.,Merchan, F. L.,Tejero, T.
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p. 867 - 870
(2007/10/02)
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