98187-18-9Relevant articles and documents
Structure-Based Optimization of a Small Molecule Antagonist of the Interaction between WD Repeat-Containing Protein 5 (WDR5) and Mixed-Lineage Leukemia 1 (MLL1)
Getlik, Matth?us,Smil, David,Zepeda-Velázquez, Carlos,Bolshan, Yuri,Poda, Gennady,Wu, Hong,Dong, Aiping,Kuznetsova, Ekaterina,Marcellus, Richard,Senisterra, Guillermo,Dombrovski, Ludmila,Hajian, Taraneh,Kiyota, Taira,Schapira, Matthieu,Arrowsmith, Cheryl H.,Brown, Peter J.,Vedadi, Masoud,Al-Awar, Rima
supporting information, p. 2478 - 2496 (2016/04/10)
WD repeat-containing protein 5 (WDR5) is an important component of the multiprotein complex essential for activating mixed-lineage leukemia 1 (MLL1). Rearrangement of the MLL1 gene is associated with onset and progression of acute myeloid and lymphoblastic leukemias, and targeting the WDR5-MLL1 interaction may result in new cancer therapeutics. Our previous work showed that binding of small molecule ligands to WDR5 can modulate its interaction with MLL1, suppressing MLL1 methyltransferase activity. Initial structure-activity relationship studies identified N-(2-(4-methylpiperazin-1-yl)-5-substituted-phenyl) benzamides as potent and selective antagonists of this protein-protein interaction. Guided by crystal structure data and supported by in silico library design, we optimized the scaffold by varying the C-1 benzamide and C-5 substituents. This allowed us to develop the first highly potent (Kdisp 100 nM) small molecule antagonists of the WDR5-MLL1 interaction and demonstrate that N-(4-(4-methylpiperazin-1-yl)-3′-(morpholinomethyl)-[1,1′-biphenyl]-3-yl)-6-oxo-4-(trifluoromethyl)-1,6-dihydropyridine-3-carboxamide 16d (OICR-9429) is a potent and selective chemical probe suitable to help dissect the biological role of WDR5.
Tetrahydronaphthyridinyl-carboxamides having anti-convulsant activity
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, (2008/06/13)
Compounds of formula (I) and pharmaceutically acceptable salts and solvates: where R1is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), phenyl-C1-4alkyl-, C1-6alkenyl, C1-6
Anti-convulsant isoquinolyl-benzamide derivatives
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, (2008/06/13)
Compounds of formula (I) and pharmaceutically acceptable salts thereof, where R1is hydrogen, C1-6alkyl (optionally substituted by hydroxy or C1-4alkoxy), C1-6alkenyl, C1-6alkynyl, C1-6alkylCO—, formyl, CF3CO— or C1-6alkylSO2—; R2is hydrogen or up to three substituents selected from halogen, NO2, CN, N3, CF3O—, CF3S—, CF3CO—, trifluoromethyldiazirinyl, C 1-6?alkyl, C1-6alkenyl, C1-6alkynyl, C1-6perfluoroalkyl, C3-6cycloalkyl, C3-6cycloalkyl-C1-4alkyl-, C1-6alkylO—, C1-6alkylCO—, C3-6cycloalkylO—, C3-6cycloalkylCO—, C3-6cycloalkyl-C1-4alkylO—, C3-6cycloalkyl-C1-4alkylCO—, phenyl, phenoxy, benzyloxy, benzoyl, phenyl-C1-4alkyl-, C1-6alkylS—, C1-6alkylSO2—, (C1-4alkyl)2NSO2—, (C1-4alkyl)NHSO2—, (C1-4alkyl)2NCO—, (C1-4alkyl)NHCO— or CONH2; or —NR5R6where R5is hydrogen or C1-4alkyl, and R6is hydrogen, C1-4alkyl, formyl, —CO2C1-4alkyl or —COC1-4alkyl; or two R2groups together form a carbocyclic ring that is saturated or unsaturated and unsubstituted or substituted by —OH or ═O; and the two R3groups and the two R4groups are each independently hydrogen or C1-6alkyl or the two R3groups and/or the two R4groups together form a C3-6spiroalkyl group provided that at least one R3and R4group is not hydrogen, are useful in the treatment and prophylaxis of epilepsy and other disorders.
