The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents.

Purpose: Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due to their nonenzymatic 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 antilymphoma activity.

Experimental Design: The study included preclinical activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on models; and transcriptome and coimmunoprecipitation experiments.

Results: YK-4-279 and TK-216 demonstrated an antitumor activity across several lymphoma cell lines, which we validated . 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 inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with and antitumor 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.