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Clin Cancer Res. 2019 Aug 15;25(16):5167-5176. doi: 10.1158/1078-0432.CCR-18-2718. Epub 2019 Jun 10.

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

Author information

1
Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland.
2
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
3
Oncternal Therapeutics, San Diego, California.
4
Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
5
Departments of Oncology and Pediatrics, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC.
6
Università della Svizzera italiana, Institute of Biomedical Research, Bellinzona, Switzerland.
7
Dalle Molle Institute for Artificial Intelligence, Manno, Switzerland.
8
Department of Cell Biology, Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, New York.
9
Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
10
Università della Svizzera italiana, Institute of Oncology Research, Bellinzona, Switzerland. frbertoni@mac.com.
#
Contributed equally

Abstract

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 in vitro activity screening on a large panel of cell lines, both as single agent and in combination; validation experiments on in vivo 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 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 inhibitor YK-4-279 and its clinical derivative TK-216 represent a new class of agents with in vitro and in vivo 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.

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