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

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