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

Filippo Spriano, Elaine Y. L. Chung, Eugenio Gaudio, Chiara Tarantelli, Luciano Cascione, Sara Napoli, Katti Jessen, Laura Carrassa, Valdemar Priebe, Giulio Sartori, Garrett Graham, Saravana P. Selvanathan, Andrea Cavalli, Andrea Rinaldi, Ivo Kwee, Monica Testoni, Davide Genini, B. Hilda Ye, Emanuele Zucca, Anastasios StathisBrian Lannutti, Jeffrey A. Toretsky, Francesco Bertoni

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5167-5176
Number of pages10
JournalClinical Cancer Research
Volume25
Issue number16
DOIs
StatePublished - Aug 15 2019

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Lymphoma
Transcription Factors
RNA Helicases
Cell Line
Germinal Center
Lymphoma, Large B-Cell, Diffuse
B-Cell Lymphoma
Transcriptome
Neoplasms
Proteins
Research Design
YK 4-279
Pharmaceutical Preparations
In Vitro Techniques
lenalidomide
4-(4-((2-(4-chlorophenyl)-4,4-dimethylcyclohex-1-en-1-yl)methyl)piperazin-1-yl)-N-((3-nitro-4-((tetrahydro-2H-pyran-4-ylmethyl)amino)phenyl)sulfonyl)-2-(1H-pyrrolo(2,3-b)pyridin-5-yloxy)benzamide
blocking factor

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Spriano, F., Chung, E. Y. L., Gaudio, E., Tarantelli, C., Cascione, L., Napoli, S., ... Bertoni, F. (2019). The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents. Clinical Cancer Research, 25(16), 5167-5176. https://doi.org/10.1158/1078-0432.CCR-18-2718

The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents. / Spriano, Filippo; Chung, Elaine Y. L.; Gaudio, Eugenio; Tarantelli, Chiara; Cascione, Luciano; Napoli, Sara; Jessen, Katti; Carrassa, Laura; Priebe, Valdemar; Sartori, Giulio; Graham, Garrett; Selvanathan, Saravana P.; Cavalli, Andrea; Rinaldi, Andrea; Kwee, Ivo; Testoni, Monica; Genini, Davide; Ye, B. Hilda; Zucca, Emanuele; Stathis, Anastasios; Lannutti, Brian; Toretsky, Jeffrey A.; Bertoni, Francesco.

In: Clinical Cancer Research, Vol. 25, No. 16, 15.08.2019, p. 5167-5176.

Research output: Contribution to journalArticle

Spriano, F, Chung, EYL, Gaudio, E, Tarantelli, C, Cascione, L, Napoli, S, Jessen, K, Carrassa, L, Priebe, V, Sartori, G, Graham, G, Selvanathan, SP, Cavalli, A, Rinaldi, A, Kwee, I, Testoni, M, Genini, D, Ye, BH, Zucca, E, Stathis, A, Lannutti, B, Toretsky, JA & Bertoni, F 2019, 'The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents', Clinical Cancer Research, vol. 25, no. 16, pp. 5167-5176. https://doi.org/10.1158/1078-0432.CCR-18-2718
Spriano F, Chung EYL, Gaudio E, Tarantelli C, Cascione L, Napoli S et al. The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents. Clinical Cancer Research. 2019 Aug 15;25(16):5167-5176. https://doi.org/10.1158/1078-0432.CCR-18-2718
Spriano, Filippo ; Chung, Elaine Y. L. ; Gaudio, Eugenio ; Tarantelli, Chiara ; Cascione, Luciano ; Napoli, Sara ; Jessen, Katti ; Carrassa, Laura ; Priebe, Valdemar ; Sartori, Giulio ; Graham, Garrett ; Selvanathan, Saravana P. ; Cavalli, Andrea ; Rinaldi, Andrea ; Kwee, Ivo ; Testoni, Monica ; Genini, Davide ; Ye, B. Hilda ; Zucca, Emanuele ; Stathis, Anastasios ; Lannutti, Brian ; Toretsky, Jeffrey A. ; Bertoni, Francesco. / The ETS inhibitors YK-4-279 and TK-216 are novel antilymphoma agents. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 16. pp. 5167-5176.
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AU - Spriano, Filippo

AU - Chung, Elaine Y. L.

AU - Gaudio, Eugenio

AU - Tarantelli, Chiara

AU - Cascione, Luciano

AU - Napoli, Sara

AU - Jessen, Katti

AU - Carrassa, Laura

AU - Priebe, Valdemar

AU - Sartori, Giulio

AU - Graham, Garrett

AU - Selvanathan, Saravana P.

AU - Cavalli, Andrea

AU - Rinaldi, Andrea

AU - Kwee, Ivo

AU - Testoni, Monica

AU - Genini, Davide

AU - Ye, B. Hilda

AU - Zucca, Emanuele

AU - Stathis, Anastasios

AU - Lannutti, Brian

AU - Toretsky, Jeffrey A.

AU - Bertoni, Francesco

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