In eukaryotes, post-translational modification of histones is critical for regulation of chromatin structure and gene expression. EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and is involved in repressing gene expression through methylation of histone H3 on lysine 27 (H3K27). EZH2 overexpression is implicated in tumorigenesis and correlates with poor prognosis in several tumour types. Additionally, somatic heterozygous mutations of Y641 and A677 residues within the catalytic SET domain of EZH2 occur in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma. The Y641 residue is the most frequently mutated residue, with up to 22% of germinal centre B-cell DLBCL and follicular lymphoma harbouring mutations at this site. These lymphomas have increased H3K27 tri-methylation (H3K27me3) owing to altered substrate preferences of the mutant enzymes. However, it is unknown whether specific, direct inhibition of EZH2 methyltransferase activity will be effective in treating EZH2 mutant lymphomas. Here we demonstrate that GSK126, a potent, highly selective, S-adenosyl-methionine-competitive, small-molecule inhibitor of EZH2 methyltransferase activity, decreases global H3K27me3 levels and reactivates silenced PRC2 target genes. GSK126 effectively inhibits the proliferation of EZH2 mutant DLBCL cell lines and markedly inhibits the growth of EZH2 mutant DLBCL xenografts in mice. Together, these data demonstrate that pharmacological inhibition of EZH2 activity may provide a promising treatment for EZH2 mutant lymphoma.

This article describes efficient and mild protocols for preparing polysubstituted imidazoles in a single pot from aryl-substituted tosylmethyl isocyanide (TosMIC) reagents and imines generated in situ. Traditional imine-forming reactions employing virtually any aldehyde and amine followed by addition of the TosMIC reagent delivers 1,4,5-trisubstituted imidazoles with predictable regiochemistry. Employing chiral amines and aldehydes, particularly those derived from alpha-amino acids, affords imidazoles with asymmetric centers appended to N-1 or C-5 with excellent retention of chiral purity. 1,4-Disubstituted imidazoles are also readily prepared by a simple variant of the above procedure. Selecting glyoxylic acid as the aldehyde component of this procedure leads to intermediates such as 48, which readily undergo decarboxylation and elimination of the tosyl moiety to deliver 1,4-disubstituted imidazoles in high yields. Alternatively, using NH(4)OH as the amine component in conjunction with a variety of aldehydes delivers 4, 5-disubstituted imidazoles in moderate to good yields in a single pot while avoiding the need for protecting groups. Finally, the facile preparation of mono- and disubstituted oxazoles from these TosMIC reagents and aldehydes is described.

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α‐tosylbenzyl isocyanide intermediate: p‐toluenesulfinic acid intermediate: N‐(α‐tosylbenzyl)formamide product: α‐tosylbenzyl isocyanide

Several highly substituted imidazoles have been under investigation at GlaxoSmithKline as potential therapies for the treatment of rheumatoid arthritis and have spawned the need for a general synthetic method for their preparation on a multikilogram scale. We describe herein the optimization of a general method for the preparation of aryl-substituted TosMIC reagents and the ease with which they undergo [3+2] cycloadditions with a host of imines, prepared in situ, to generate densely functionalized imidazoles with various substitution patterns in a completely regioselective manner.