824960-50-1Relevant academic research and scientific papers
Synthesis, optimization, and evaluation of novel small molecules as antagonists of WDR5-MLL interaction
Bolshan, Yuri,Getlik, Matthaeus,Kuznetsova, Ekaterina,Wasney, Gregory A.,Hajian, Taraneh,Poda, Gennadiy,Nguyen, Kong T.,Wu, Hong,Dombrovski, Ludmila,Dong, Aiping,Senisterra, Guillermo,Schapira, Matthieu,Arrowsmith, Cheryl H.,Brown, Peter J.,Al-Awar, Rima,Vedadi, Masoud,Smil, David
supporting information, p. 353 - 357 (2013/04/24)
The WD40-repeat protein WDR5 plays a critical role in maintaining the integrity of MLL complexes and fully activating their methyltransferase function. MLL complexes, the trithorax-like family of SET1 methyltransferases, catalyze trimethylation of lysine 4 on histone 3, and they have been widely implicated in various cancers. Antagonism of WDR5 and MLL subunit interaction by small molecules has recently been presented as a practical way to inhibit activity of the MLL1 complex, and N-(2-(4-methylpiperazin-1-yl)-5-substituted- phenyl) benzamides were reported as potent and selective antagonists of such an interaction. Here, we describe the protein crystal structure guided optimization of prototypic compound 2 (Kdis = 7 μM), leading to identification of more potent antagonist 47 (Kdis = 0.3 μM).
