- Exploration of a 14-3-3 PPI Pocket by Covalent Fragments as Stabilizers
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The systematic discovery of functional fragments binding to the composite interface of protein complexes is a first critical step for the development of orthosteric stabilizers of protein-protein interactions (PPIs). We have previously shown that disulfide trapping successfully yielded covalent stabilizers for the PPI of 14-3-3 with the estrogen receptor ERα. Here we provide an assessment of the composite PPI target pocket and the molecular characteristics of various fragments binding to a specific subpocket. Evaluating structure-activity relationships highlights the basic principles for PPI stabilization by these covalent fragments that engage a relatively large and exposed binding pocket at the protein/peptide interface with a "molecular glue"mode of action.
- Sijbesma, Eline,Hallenbeck, Kenneth K.,Andrei, Sebastian A.,Rust, Reanne R.,Adriaans, Joris M. C.,Brunsveld, Luc,Arkin, Michelle R.,Ottmann, Christian
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supporting information
p. 976 - 982
(2021/05/27)
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- PROTEIN-PROTEIN INTERACTION STABILIZERS
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Provided herein, inter alia, are stabilizers of protein-protein interactions and methods of identifying and using the same.
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Paragraph 0921-0922
(2021/10/11)
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- Discovery of a series of 1H-pyrrolo[2,3-b]pyridine compounds as potent TNIK inhibitors
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In an in-house screening, 1H-pyrrolo[2,3-b]pyridine scaffold was found to have high inhibition on TNIK. Several series of compounds were designed and synthesized, among which some compounds had potent TNIK inhibition with IC50 values lower than 1 nM. Some compounds showed concentration-dependent characteristics of IL-2 inhibition. These results provided new applications of TNIK inhibitors and new prospects of TNIK as a drug target.
- Yang, Bowen,Wu, Qian,Huan, Xiajuan,Wang, Yingqing,Sun, Yin,Yang, Yueyue,Liu, Tongchao,Wang, Xin,Chen, Lin,Xiong, Bing,Zhao, Dongmei,Miao, Zehong,Chen, Danqi
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- Synthesis, characterization and biological evaluation of ureidofibrate-like derivatives endowed with peroxisome proliferator-activated receptor activity
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A series of ureidofibrate-like derivatives was prepared and assayed for their PPAR functional activity. A calorimetric approach was used to characterize PPARγ-ligand interactions, and docking experiments and X-ray studies were performed to explain the obs
- Porcelli,Gilardi,Laghezza,Piemontese,Mitro,Azzariti,Altieri,Cervoni,Fracchiolla,Giudici,Guerrini,Lavecchia,Montanari,Di Giovanni,Paradiso,Pochetti,Simone,Tortorella,Crestani,Loiodice
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experimental part
p. 37 - 54
(2012/03/09)
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- Synthesis and preliminary antihyperlipidaemic activities evaluation of andrographolide derivatives
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Recent studies indicated that andrographolide was a potential antihyperlipidaemic therapeutic agent. In the paper, the synthesis of a series of andrographolide derivatives was described and their antihyperlipidaemic activities were evaluated in vivo. As compared with TG, TC, HDL-C and LDL-C concentrations, some of the derivatives exhibited better antihyperlipidaemic effects than positive control atromide. Therein, compound 6i, which was the most potent compound, could serve as a new lead for further development of antihyperlipidaemic agents.
- Wang, Bin,Tang, Chunlei,Han, Yaodan,Guo, Ruzhou,Qian, Hai,Huang, Wenlong
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experimental part
p. 293 - 298
(2012/07/30)
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- NOVEL COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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[1,2,4]Triazolo[1,5-a]pyridine compounds are disclosed that have a formula represented by the following: (I) These compound may be prepared as a pharmaceutical composition, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, diseases involving cartilage degradation, bone and/or joint degradation, for example osteoarthritis; and/or conditions involving inflammation or immune responses, such as Crohn's disease, rheumatoid arthritis, psoriasis, allergic airways disease (e.g. asthma, rhinitis), juvenile idiopathic arthritis, colitis, inflammatory bowel diseases, endotoxin-driven disease states (e.g. complications after bypass surgery or chronic endotoxin states contributing to e.g. chronic cardiac failure), diseases involving impairment of cartilage turnover (e.g. diseases involving the anabolic stimulation of chondrocytes), congenital cartilage malformations, diseases associated with hypersecretion of IL6 and transplantation rejection (e.g. organ transplant rejection) and proliferative diseases.
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Page/Page column 72
(2010/04/03)
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- CCR10 ANTAGONISTS
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The invention relates to a compound of formula (I) or a tautomer thereof or a pharmaceutically acceptable salt thereof, wherein R1 to R11, W, X, Y, Z, and n are as defined herein. The invention also relates to methods of using the compounds of formula (I) and compositions thereof to treat various diseases and disorders in a patient. The invention also relates to processes for preparing the compounds of formula (I) and intermediates useful in these processes.
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Page/Page column 65
(2009/05/28)
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- Liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives from poly(ethylene glycol) supported 2-bromo-2-methylpropanoate
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An efficient liquid-phase synthesis of 2-methyl-2-aryloxypropanoic acid derivatives with good yields and high purity on soluble polyethylene glycol (PEG) has been developed by treatment of PEG-bound 2-bromo-2-methylpropanoate with phenoxides in the presence of a catalytic amount of NBu4I and KI, and subsequent cleavage from the PEG.
- Huang, Bin,Huang, Pei-Gang,Sheng, Shou-Ri,Wang, Qiu-Ying,Guo, Lei,Jiang, Shao-Hua
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p. 575 - 578
(2008/02/11)
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- 2-AMINOQUINAZOLINE DERIVATIVE
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The present invention provides a compound represented by Formula (I) (wherein R 1 and R 2 are the same or different, and each represents a hydrogen atom, substituted or unsubstituted lower alkyl and the like, R 3 represents substituted or unsubstituted aryl, a substituted or unsubstituted aromatic heterocyclic group and the like, R 4 and R 5 are the same or different, and each represents a hydrogen atom, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted aryl and the like, proviso that they are not simultaneously hydrogen atoms, and R 6 represents hydroxy or substituted or unsubstituted lower alkoxy), or a pharmaceutically acceptable salt thereof and the like.
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Page/Page column 48
(2010/11/24)
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- INDOLES USEFUL IN THE TREATMENT OF INFLAMMATION
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There is provided a compound of formula: (I), wherein X, R1, R2, R3, R4, R5 and R6 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of microsomal prostaglandin E synthase-1 is desired and/or required, and particularly in the treatment of inflammation.
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Page/Page column 61
(2010/02/15)
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- Water-based biphasic media for exothermic reactions: Green chemistry strategy for the large scale preparation of clofibric acid and analogues
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A water-based biphasic reaction process has been developed for conducting exothermic reactions without organic solvents. This procedure is rapid, simple, and suitable for small scale synthesis as well as larger (multi-molar) scale reactions. The preparation of several hundred grams of clofibric acid and analogues by this eco-friendly and energy-efficient procedure is described. Smaller amounts of these compounds were prepared by the friction-activated 'Grindstone Chemistry' method described previously.
- Bose, Ajay K.,Manhas, Maghar S.,Ganguly, Subhendu N.,Pednekar, Suhas,Mandadi, Arun
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p. 3011 - 3013
(2007/10/03)
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- ipso Nitration in p-halophenyl ethers
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Addition of nitronium ion ipso to halogen occurs on nitration of the p-haloanisoles in acetic anhydride at -60 deg C.In the cases of p-fluoro- and p-chloro-anisole, addition of the nitronium ion is reversible and only small amounts of ipso products are obtained.With p-bromoanisole nitrodebromination occurs.When p-halophenyl ethers containing a trapping substituent, e.g., 2-(4-chlorophenoxy)-2-methylpropanoic acid, are used as substrates, substantial amounts of the spiro diene with nitro ipso to halogen, e.g., 3,3-dimethyl-8-chloro-8-nitro-1,4-dioxaspirodeca-6,9-dien-2-one, can be isolated.The results demonstrate that extensive ipso attack at the halogen-substituted position is general in the nitration of p-halophenyl ethers.Key words: ipso nitration, ether, diene, p-haloanisole.
- Clewley, Robin G.,Fischer, Alfred,Henderson, George N.
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p. 1472 - 1479
(2007/10/02)
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