The novel BET inhibitor UM-002 reduces glioblastoma cell proliferation and invasion

Matthew J. Rybin,Nagi G. Ayad,Robert K. Suter,Jann N. Sarkaria,Yangbo Feng,Anna M. Jermakowicz,Zane Zeier

doi:10.1038/s41598-021-02584-6

Abstract

Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). Although several BET inhibitors have entered clinical trials, few are brain penetrant. We have generated UM-002, a novel brain penetrant BET inhibitor that reduces GBM cell proliferation in vitro and in a human cerebral brain organoid model. Since UM-002 is more potent than other BET inhibitors, it could potentially be developed for GBM treatment. Furthermore, UM-002 treatment reduces the expression of cell-cycle related genes in vivo and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNA-sequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. Importantly, they also provide an integrated dataset that combines in vitro and ex vivo studies with in vivo single-cell RNA-sequencing to characterize a novel BET inhibitor in GBM.

Highlights

Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM)
We identified a previously developed bromodomain-containing protein 4 (BRD4) inhibitor, and we discovered that there is potential for increasing potency of this molecule while retaining properties of known brain penetrant compounds, yielding the novel BET inhibitor UM-00224–26 (Fig. 1A)
These studies suggest that UM-002 is a novel selective brain penetrant BET inhibitor, that reduces GBM cell proliferation in vitro

Summary

Introduction

Bromodomain and extraterminal domain (BET) proteins have emerged as therapeutic targets in multiple cancers, including the most common primary adult brain tumor glioblastoma (GBM). UM-002 treatment reduces the expression of cell-cycle related genes in vivo and reduces the expression of invasion related genes within the non-proliferative cells present in tumors as measured by single cell RNAsequencing. These studies suggest that BET inhibition alters the transcriptional landscape of GBM tumors, which has implications for designing combination therapies. We and others have demonstrated that epigenetic reader proteins with bromodomain and extra-terminal (BET) domains are promising therapeutic targets in GBM2–10 One such BET protein, bromodomain-containing protein 4 (BRD4), is a target in multiple cancers.

Methods

Results

Conclusion