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

Abstract

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.

Thinking Outside the Box: Indirect Myc Modulation in Canine B-Cell Lymphoma

“…In addition, MZ1 affected the cell viability of CLBL-1 and KLR-1201 cells in a significant concentrationand time-dependent manner. This finding aligns with results obtained with BET degraders in human lymphomas, where BRD4 is selectively degraded by drugs with mechanisms of action involving E3 ligase recruitment to the proteasome [19].…”

“…MZ1 derived from JQ1, which exhibits the capacity to degrade BRD2, BRD3, and BRD4 [16]. It demonstrated more potent protein degradation activities compared to JQ1 and shows significant cytotoxicity against colorectal cancer, triple-negative breast cancer, and lymphoma in humans [16][17][18][19].…”

Thinking Outside the Box: Indirect Myc Modulation in Canine B-Cell Lymphoma

“…In addition, MZ1 affected the cell viability of CLBL-1 and KLR-1201 cells in a significant concentration-and time-dependent manner. This finding aligns with results obtained with BET degraders in human lymphomas, where BRD4 is selectively degraded by drugs with mechanisms of action involving E3 ligase recruitment to the proteasome [19].…”

“…MZ1 is derived from JQ1, which exhibits the capacity to degrade BRD2, BRD3, and BRD4 [16]. It demonstrates more potent protein degradation activities compared to JQ1 and shows significant cytotoxicity against colorectal cancer, triple-negative breast cancer, and lymphoma in humans [16][17][18][19].…”

PROTACs in Epigenetic Cancer Therapy: Current Status and Future Opportunities

“…In triple-negative breast and ovarian cancer cell lines, mez1 inhibits the growth of both sensitive and resistant cells and acts on allogeneic tumors in vitro [ 40 ]. MZ1 has exhibited excellent antitumor effects in B-cell-like diffuse large B-cell lymphoma, neuroblastoma, and colon cancer cells [ 51 , 52 , 53 ]. In Human epidermal growth factor receptor 2 (HER2) positive cells, the combined use of MZ1 and trastuzumab could enhance the induction of apoptosis, leading to better inhibition of tumors.…”