Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734

Filippo Spriano, Eugenio Gaudio, Luciano Cascione, Chiara Tarantelli, Federica Melle, Giovanna Motta, Valdemar Priebe, Andrea Rinaldi, Gaetanina Golino, Afua Adjeiwaa Mensah, Luca Aresu, Emanuele Zucca, Stefano Pileri, Michael Witcher, Bill Brown, Claes Wahlestedt, Francis Giles, Anastasios Stathis, Francesco Bertoni

Research output: Contribution to journalArticlepeer-review

Abstract

Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/ CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.

Original languageEnglish
Pages (from-to)4124-4135
Number of pages12
JournalBlood advances
Volume4
Issue number17
DOIs
Publication statusPublished - Sep 8 2020

ASJC Scopus subject areas

  • Hematology

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