1193639-06-3Relevant articles and documents
Discovery of WD Repeat-Containing Protein 5 (WDR5)-MYC Inhibitors Using Fragment-Based Methods and Structure-Based Design
Chacón Simon, Selena,Wang, Feng,Thomas, Lance R.,Phan, Jason,Zhao, Bin,Olejniczak, Edward T.,MacDonald, Jonathan D.,Shaw, J. Grace,Schlund, Caden,Payne, William,Creighton, Joy,Stauffer, Shaun R.,Waterson, Alex G.,Tansey, William P.,Fesik, Stephen W.
, p. 4315 - 4333 (2020)
The frequent deregulation of MYC and its elevated expression via multiple mechanisms drives cells to a tumorigenic state. Indeed, MYC is overexpressed in up to ?50% of human cancers and is considered a highly validated anticancer target. Recently, we discovered that WD repeat-containing protein 5 (WDR5) binds to MYC and is a critical cofactor required for the recruitment of MYC to its target genes and reported the first small molecule inhibitors of the WDR5-MYC interaction using structure-based design. These compounds display high binding affinity, but have poor physicochemical properties and are hence not suitable for in vivo studies. Herein, we conducted an NMR-based fragment screening to identify additional chemical matter and, using a structure-based approach, we merged a fragment hit with the previously reported sulfonamide series. Compounds in this series can disrupt the WDR5-MYC interaction in cells, and as a consequence, we observed a reduction of MYC localization to chromatin.
WDR5-MYC INHIBITORS
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Paragraph 0098; 00122-00123; 00129, (2021/05/29)
Substituted N-heteroaryl sulfonamide compounds inhibit WDR5-MYC interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject such as cancer cell proliferation.
IMIDAZOLE-CONTAINING INHIBITORS OF ALK2 KINASE
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Page/Page column 634; 635, (2019/01/08)
Disclosed are compounds of formula (I), (II), (III), and (IV), and pharmaceutically acceptable salts thereof. The compounds are inhibitors of ALK2 kinase. Also provided are pharmaceutical compositions comprising a compound of formula (I), (II), (III), or (IV), or pharmaceutically acceptable salt thereof, and methods involving use of the compounds or pharmaceutically acceptable salts thereof and compositions in the treatment and prevention of various diseases and conditions, such as fibrodysplasia ossificans progressiva.
Potent and cellularly active 4-aminoimidazole inhibitors of cyclin-dependent kinase 5/p25 for the treatment of Alzheimer's disease
Helal, Christopher J.,Kang, Zhijun,Lucas, John C.,Gant, Thomas,Ahlijanian, Michael K.,Schachter, Joel B.,Richter, Karl E.G.,Cook, James M.,Menniti, Frank S.,Kelly, Kristin,Mente, Scot,Pandit, Jay,Hosea, Natalie
scheme or table, p. 5703 - 5707 (2010/04/30)
Utilizing structure-based drug design, a 4-aminoimidazole heterocyclic core was synthesized as a replacement for a 2-aminothiazole due to potential metabolically mediated toxicity. The synthetic route utilized allowed for ready synthesis of 1-substituted-4-aminoimidazoles. SAR exploration resulted in the identification of a novel cis-substituted cyclobutyl group that gave improved enzyme and cellular potency against cdk5/p25 with up to 30-fold selectivity over cdk2/cyclin E.
