BRD4 PROTAC Degradation Agent GNE-987 Inhibits Acute Myeloid Leukemia by Targeting Super Enhancers

Abstract

Background: Acute myeloid leukemia (AML) is a common hematological malignancy in children, with poor treatment effect and poor prognosis. Recent studies have shown that bromodomain and terminal protein inhibitors are promising antitumor drugs. As a new type of BRD4 PROTAC degradation agent, GNE-987 can slow down the growth rate of a variety of tumors and cause apoptosis, which has broad clinical prospects. However, the role of GNE-987 in AML is unclear. This study aims to explore the therapeutic effect of GNE-987 in AML and its underlying mechanism.Methods: By studying public databases, the prognostic significance of BRD4 and the correlation between AML were evaluated, and the relationship between BRD4 and the overall survival rate of AML patients was also analyzed. After adding GNE-987 to the AML cell line, cell proliferation slowed down, cycle disorder, and apoptosis increased. In the cells treated with GNE-987, western-blotting was used to detect BRD2, BRD3, BRD4 and PARP proteins. The effect of GNE-987 on AML cells was analyzed in vivo. RNA-seq and chromatin immunoprecipitation sequencing (ChIP-seq) confirmed the function and molecular pathway of GNE-987 in processing AML. Results: Compared with healthy donors, the expression of BRD4 in children's AML samples was higher than that of healthy donors. The high expression of BRD4 indicates a poor prognosis. GNE-987 inhibits AML cell proliferation by inhibiting the cell cycle and inducing apoptosis. BRD2, BRD3 and BRD4 are consistent with the decreased expression of VHL in AML cells. Compared with JQ1 and ARV-825, GNE-987 has a lower IC50 in AML cells. In the AML xenograft model, GNE-987 significantly reduced the liver and spleen infiltration of leukemia cells, increased the survival time of mice, and caused BRD4, Ki67 dysregulation and caspase3 activation. According to the analysis of RNA-seq and ChIP-seq, GNE-987 can inhibit AML by targeting numerous super-enhancers.Conclusions: GNE-987 has strong anti-tumor activity in AML cell lines and primary child AML samples. GNE-987 works by degrading the BET protein, thereby effectively inhibiting the expression of super enhancers and related oncogenes (such as LYL1). These results indicate that GNE-987 has very broad prospects for the treatment of AML.

Super-enhancers in esophageal carcinoma: Transcriptional addictions and therapeutic strategies

“…The first oral PROTACs (ARV-110, NCT03888612 & ARV-471, NCT04072952) have achieved encouraging benefit for prostate and breast cancer treatment in clinical trials ( 92 ). The newly developed GNE987, and PROTAC pan-BET degrader, have been showing good potency against several cancers, including hematological malignancies ( 93 , 94 ), neuroblastoma ( 95 ), and prostate carcinoma ( 96 ). Additionally, MZ1, a PROTAC BET degrader, was previously identified unexpectedly degradation of BRD4 over other members of BET family, such as BRD2 and BRD3 ( 97 ).…”