GSK126 - CAS 1346574-57-9

McCabe et al. reported that GSK126 is a potent and highly selective inhibitor of Ezh2 methyltransferase activity that decreases the global H3K27me3 level and induces pharmacological inhibition of proliferation in the Ezh2 mutant lymphoma. GSK126 also reduces H3K27me3 levels in wild-type DLBCL cell lines. In view of the low expression of Ezh2 in normal resting populations, selective pharmacological intervention to inhibit Ezh2 activity in both wild-type and mutant lymphomas is a promising approach that warrants further research.

GSK126 is a newly designed specific inhibitor of EZH2. It has been reported that GSK126 markedly inhibit progression of lymphoma both in vitro and vivo. However, the effect of GSK126 on solid tumor remains elusive. In addition, although GSK126 used alone or combined with other anticancer drugs has been shown to inhibit the cancer progression in prostate and non-small cell lung cancers, its effects and related mechanisms on metastasis have not been explored. In the present study, we investigated the effects of GSK126 on migration and angiogenesis as well as its possible mechanisms in gastric and lung cancers.

After the development of the ‘‘first generation’’ of epigenetic drugs, such as DNA methylation and HDAC inhibitors that have a broad spectrum of epigenetic activities, currently, the ‘‘second generation’’ of cancer epigenetic agents targeting specific histone methylation or demethylation enzymes has gained attention in the field of epigenetic cancer therapy. For instance, small molecule inhibitors targeting EZH2 H3K27 methyltransferase activity, such as GSK126, EPZ005687, and EPZ-6438, have shown anti-tumor activity in various human cancers, including acute myeloma and lymphomas, and indeed, EPZ-6438 has entered a phase 1/2 clinical trial in patients with advanced solid tumors or with B-cell lymphomas (NCT01897571). Selective inhibitors of the H3K79 methyltransferase DOT1L have also emerged as new epigenetic drugs that effectively target MLL-rearranged leukemia, and EPZ-5676, the most advanced DOT1L inhibitor, is undergoing a phase 1 clinical trial in acute leukemia patients (NCT01684150). In acute myeloid leukemia (AML), the LSD1 inhibitor GSK2879552 is now entering a clinical trial (NCT02177812). Recently, GSKJ4, a KDM6A/B inhibitor (JMJD3), which prevents the upregulation of Snail, has been developed as a novel anticancer drug. An inhibitor of bromodomain-containing epigenetic reader BET proteins has also emerged as a promising cancer drug and is beginning clinical evaluation. Because these epigenetic regulators have been considered crucial modulators in the EMT program as described in the previous section, it is possible that the epigenetic drugs targeting these enzymes can be effective for inhibiting EMT-induced tumor progression.

As we hope to have shown in this review, miRNA analysis in T-cell lymphoma/leukemias remains insufficiently understood. Nevertheless, previous reports of deep associations between miRNAs and well-defined T-cell lymphomas strongly suggest that such dysregulation may play crucial roles in undefined T-cell lymphoma subtypes as well. Notably, products that are detected as targets of miRNA may represent therapeutic molecular targets in T-cell lymphoma [e.g., inhibitor of EZH2 methyltransferase activity (GSK126) against ATLL; bortezomib against PTCL-NOS or CTCL]. Further, miRNAs or antisense miRNAs may also represent novel candidate agents for the treatment of cancer, although appropriate delivery systems have yet to be established. As miRNA plays essential roles in normal and cancer cells, we are confident that further studies promise evolutionary approaches to the treatment of aggressive lymphomas.