Christine Thompson

TL;DR: 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 and markedly inhibits the growth of EzH2 mutant DLBCL xenografts in mice are demonstrated.

TL;DR: This work has identified highly potent, selective, SAM-competitive, and cell-active EZH2 inhibitors, including GSK926 and GSK343, which are small molecule chemical tools that would be useful to further explore the biology of EZh2.

TL;DR: It is identified that inhibiting symmetric or asymmetric dimethylation of arginine, mediated by PRMT5 and type I proteinArginine methyltransferases (PRMTs), respectively, reduces splicing fidelity and results in preferential killing of SF-mutant leukemias over wild-type counterparts.

TL;DR: Broad anti-proliferative activity of potent, selective, reversible inhibitors of protein arginine methyltransferase 5 (PRMT5) including GSK3326595 is described in human cancer cell lines representing both hematologic and solid malignancies suggesting that the integrity of the p53-MDM4 regulatory axis defines a subset of patients that could benefit from treatment with GSK 3326595.

TL;DR: Key to the advancement of the series was the introduction of a 2-aryl group containing a basic amine onto the azaindole leading to significantly improved cellular activity leading to the identification of GSK1070916 (17k), a potent and selective ATP-competitive inhibitor of Aurora B and C.