TY  - JOUR
T1  - The bromodomain and extra-terminal domain degrader MZ1 exhibits preclinical anti-tumoral activity in diffuse large B-cell lymphoma of the activated B cell-like type
A1  - Tarantelli, Chiara
A1  - Cannas, Eleonora
A1  - Ekeh, Hillarie
A1  - Moscatello, Carmelo
A1  - Gaudio, Eugenio
A1  - Cascione, Luciano
A1  - Napoli, Sara
A1  - Rech, Cesare
A1  - Testa, Andrea
A1  - Maniaci, Chiara
A1  - Rinaldi, Andrea
A1  - Zucca, Emanuele
A1  - Stathis, Anastasios
A1  - Ciulli, Alessio
A1  - Bertoni, Francesco
Y1  - 2021///
KW  - BET
KW  - bromodomain
KW  - bromodomain-containing protein 4
KW  - lymphoma
KW  - diffuse large B-cell lymphoma
KW  - proteolysis-targeting chimeras
KW  - immuno-oncology
KW  - epigenetics
JF  - Exploration of Targeted Anti-tumor Therapy
VL  - 2
IS  - 6
SP  - 586
EP  - 601
DO  - 10.37349/etat.2021.00065
UR  - https://www.explorationpub.com/Journals/etat/Article/100265
N2  - Aim: Bromodomain and extra-terminal domain (BET) proteins are epigenetic readers that play a fundamental role in transcription regulation. Preclinical and early clinical evidence sustain BET targeting as an anti-cancer approach. BET degraders are chimeric compounds comprising of a BET inhibitor, which allows the binding to BET bromodomains, linked to a small molecule, binder for an E3 ubiquitin ligase complex, triggering BET proteins degradation via the proteasome. These degraders, called proteolysis-targeting chimeras (PROTACs), can exhibit greater target specificity compared to BET inhibitors and overcome some of their limitations, such as the upregulation of the BET proteins themselves. Here are presented data on the anti-tumor activity and the mechanism of action of the BET degrader MZ1 in diffuse large B cell lymphoma (DLBCL) of the activated B-cell like (ABC, ABC DLBCL), using a BET inhibitor as a comparison. Methods: Established lymphoma cell lines were exposed for 72 h to increasing doses of the compounds. Cell proliferation was evaluated by using an 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazoliumbromide (MTT) assay. Fluorescent-Activated Cell Sorter (FACS) analysis was performed to measure apoptotic activation and RNA sequencing (RNA-Seq) to study the transcriptional changes induced by the compounds. Results: MZ1, and not its negative control epimer cisMZ1, was very active with a median half maximal inhibitory concentration (IC50) of 49 nmol/L. MZ1 was more in vitro active than the BET inhibitor birabresib (OTX015). Importantly, MZ1 induced cell death in all the ABC DLBCL cell lines, while the BET inhibitor was cytotoxic only in a fraction of them. BET degrader and inhibitor shared partially similar changes at transcriptome level but the MZ1 effect was stronger and overlapped with that caused cyclin-dependent kinase 9 (CDK9) inhibition. Conclusions: The BET degrader MZ1 had strong cytotoxic activity in all the ABC DLBCL cell lines that were tested, and, at least in vitro, it elicited more profound effects than BET inhibitors, and encourages further investigations.
ER  -