Small Molecule Inhibitors of BRD4 for Treatment of Multiple Myeloma
Loading...
Date
2025-05
Authors
Journal Title
Journal ISSN
Volume Title
Publisher
The Ohio State University
Abstract
Cancer is a complex disease with distinct hallmarks caused by a variety of factors. Transcription factors that normally control a large array of genes required for cell development can become oncogenes if their transcription is altered. BRD4 is a transcriptional activator that is a member of the bromodomain and extra-terminal (ET) domain (BET) family of proteins. The bromodomains of BRD4 bind to acetylated lysine residues on histones and is common among chromatin binding proteins whereas the ET domain is distinct to the BET proteins. Current BRD4- based therapeutics target the bromodomain using small molecule mimics of acetylated lysine. These inhibitors have limited efficacy because of dose-limiting toxicities due to the inhibitors targeting other proteins with bromodomains. The ET domain interacts with proteins linked to lung, breast, oral, colon, and acute myeloid leukemia (AML) cancers as well as viral integrase (IN) from murine leukemia virus (MLV). Examination of the binding interface between MLV IN and the ET domain allowed for in-silico selection of potential inhibitors. These compounds were screened in leukemia cell lines leading to selection of BETi-10.
Multiple myeloma (MM) tumors are located within the bone marrow, making it difficult to treat with limited current therapies. Using a variety of MM cell lines, BETi-10 was tested for efficacy in this hematologic cancer. In addition, a BCL-2 selective inhibitor, venetoclax (ABT-199), was chosen based on its efficacy in hematologic cancers to test synergy with BETi-10. Some MM cell lines are less sensitive to venetoclax, prompting the idea that BETi-10 could increase sensitivity to the inhibitor.
While combination of BETi-10 and venetoclax treatment did not increase sensitivity in low responding MM cell lines, a switch from venetoclax-induced necroptosis to apoptosis was observed. After investigation of the effects of BRD4 inhibition on the necroptosis pathway, it was determined that the combination of BETi-10 and venetoclax can decrease the expression of key proteins in the pathway. These results suggest a new role of BETi-10 in the switch from necroptosis to the safer apoptotic route.