The ETS inhibitors YK-4-279 and TK-216 are novel anti-lymphoma agents

Clinical Cancer Research Online First Ar.. by Spriano, F., Chung, E. Y. L., Gaudi.. - 2h ago Preview

 
 
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Purpose: Transcription factors are commonly deregulated in cancer and they have been widely considered as difficult to target due to their non-enzymatic mechanism of action. Altered expression levels of members of the ETS-transcription factors are often observed in many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 and its clinical derivative TK-216, targeting ETS factors via blocking the protein-protein interaction with RNA helicases, for their anti-lymphoma activity. Experimental Design: The study included preclinical in vitroactivity screening on a large panel of cell lines, both as single agent and in combination, validation experiments on in vivomodels, transcriptome and co-immunoprecipitation experiments. Results: YK-4-279 and TK-216 demonstrated an anti-tumor activity across several lymphoma cell lines, which we validated in vivo. We observed synergistic activity when YK-4-279 and TK-216 were combined with the BCL2 inhibitor venetoclax and with the immunomodulatory drug lenalidomide. YK-4-279 and TK-216 interfere with protein interactions of ETS family members SPIB, in activated B-cell like type diffuse large B-cell lymphomas, and SPI1, in germinal center B-cell type diffuse large B-cell lymphomas. Conclusions: The ETS inhibitors YK-4-279 and its clinical derivative TK-216 represent a new class of agents with in vitroand in vivoanti-tumor activity in lymphomas. Although their detailed mechanism of action needs to be fully defined, in DLBCL they might act by targeting subtype-specific essential transcription factors.