- A focused structure-activity relationship study of psoralen-based immunoproteasome inhibitors
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The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task. Here, we describe a focused series of psoralen-based inhibitors of the β5i subunit of the immunoproteasome with different substituents placed at position 4′. The most promising compound was further evaluated through changes at position 3 of the psoralen ring. Despite a small decrease in the inhibitory potency in comparison with the parent compound, we were able to improve the selectivity against other subunits of both the immunoproteasome and the constitutive proteasome. The most potent compounds discriminated between both proteasome types in cell lysates and also showed a decrease in cytokine secretion in peripheral blood mononuclear cells.
- ?terman, Andrej,Gobec, Martina,Gobec, Stanislav,Mravljak, Janez,Ra??an, Irena Mlinari?,Schiffrer, Eva Shannon,Sosi?, Izidor
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supporting information
p. 1958 - 1965
(2019/11/20)
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- Trisubstituted Pyridinylimidazoles as Potent Inhibitors of the Clinically Resistant L858R/T790M/C797S EGFR Mutant: Targeting of Both Hydrophobic Regions and the Phosphate Binding Site
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Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure-activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
- Günther, Marcel,Lategahn, Jonas,Juchum, Michael,D?ring, Eva,Keul, Marina,Engel, Julian,Tumbrink, Hannah L.,Rauh, Daniel,Laufer, Stefan
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supporting information
p. 5613 - 5637
(2017/07/22)
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- OXADIAZINE COMPOUNDS AND METHODS OF USE THEREOF
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The present disclosure relates to oxadiazine compounds, pharmaceutical compositions comprising an effective amount of an oxadiazine compound and methods for using an oxadiazine compound in the treatment of a neurodegenerative disease, comprising administering to a subject in need thereof an effective amount of an oxadiazine compound.
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Paragraph 0831
(2016/12/26)
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- Cycloalkylthiazoles
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The invention relates to compounds of the formula: STR1 wherein R is hydrogen or lower alkyl, R1, R2, R3 and R4, independently, are hydrogen, lower alkyl, lower alkenyl, cycloalkyl or phenyl unsubstituted or substituted by up to 3 substituents independently selected from lower alkyl, lower alkoxy or halogen, or R1 and R2 taken together with the carbon atom are alkylene of 2 to 5 carbon atoms unsubstituted or substituted by lower alkyl, and n is an integer of from 0 to 3, and, when R1 is different from R2 and/or when R3 is different from R4, enantiomers, diastereomers and racemates thereof and, when R is hydrogen, salts thereof with pharmaceutically acceptable bases. The compounds of formula I and, when R is hydrogen, pharmaceutically exceptable salts thereof are useful as bronchopulmonary agents, for example, in the relief of asthma and allergic reactions.
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