- Screening of a Custom-Designed Acid Fragment Library Identifies 1-Phenylpyrroles and 1-Phenylpyrrolidines as Inhibitors of Notum Carboxylesterase Activity
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The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20z as the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8 gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitro ADME profiles.
- Mahy, William,Patel, Mikesh,Steadman, David,Woodward, Hannah L.,Atkinson, Benjamin N.,Svensson, Fredrik,Willis, Nicky J.,Flint, Alister,Papatheodorou, Dimitra,Zhao, Yuguang,Vecchia, Luca,Ruza, Reinis R.,Hillier, James,Frew, Sarah,Monaghan, Amy,Costa, Artur,Bictash, Magda,Walter, Magnus W.,Jones, E. Yvonne,Fish, Paul V.
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p. 9464 - 9483
(2020/10/19)
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- Design, synthesis and biological activities of pyrrole-3-carboxamide derivatives as EZH2 (enhancer of zeste homologue 2) inhibitors and anticancer agents
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Zeste enhancer homolog 2 (EZH2) is highly expressed in various malignant tumors, which could silence tumor suppressor genes via trimethylation of H3K27. Herein was first reported a novel series of pyrrole-3-carboxamide derivatives carrying a pyridone fragment as EZH2 inhibitors. By combining computational modeling, in vitro cellular assays and further rational structure-activity relationship exploration and optimization, compound DM-01 showed powerful inhibition towards EZH2. DM-01 was found to have significant ability to reduce the cellular H3K27me3 level in K562 cells in the Western blot test. Meanwhile, our data showed that knockdown EZH2 in A549 cells resulted in a decrease of cell sensitivity to DM-01 at 50 and 100 μM. DM-01 could also increase the transcription expression of DIRAS3 in a dose-dependent manner, a tumor suppressor in the downstream of EZH2, suggesting it was worth investigating further as a lead compound.
- Zhou, Qifan,Jia, Lina,Du, Fangyu,Dong, Xiaoyu,Sun, Wanyu,Wang, Lihui,Chen, Guoliang
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supporting information
p. 2247 - 2255
(2020/02/20)
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- BICYCLIC HETEROCYCLIC COMPOUND
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[Problem] To provide a compound useful as an active ingredient of a pharmaceutical composition for treating 11β-hydroxysteroid dehydrogenase type 1-related diseases such as dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance and the like. [Means for Solution] A bicyclic heterocyclic compound (the bicyclic heterocycle is formed when a cyclohexane ring is fused with a 5- to 6-membered monocyclic heterocycle that has only a nitrogen atom as a hetero atom) substituted with an acylamino group such as a (hetero)aroylamino group or the like or a pharmaceutically acceptable salt thereof was found to have an excellent selective inhibitory action against 11β-HSD1. Accordingly, the bicyclic heterocyclic compound of the present invention can be used for treating dementia, schizophrenia, depression, pain (particularly, neuropathic pain or fibromyalgia), diabetes (particularly, type II diabetes mellitus), insulin resistance, and the like.
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Paragraph 0182; 0247
(2014/09/16)
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