Dose optimization of MK-8628 (OTX015), a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins, in patients (pts) with recurrent glioblastoma (GB).

Histone lysine acetylation is critical in regulating transcription. Dysregulation of this process results in aberrant gene expression in various diseases, including cancer. The bromodomain, present in several proteins, recognizes promotor lysine acetylation and recruits other transcription factors. The bromodomain extra-terminal (BET) family of proteins consists of four conserved mammalian members that regulate transcription of oncogenes such as MYC and the NUT fusion oncoprotein. Targeting the acetyl-lysine-binding property of BET proteins is a potential therapeutic approach of cancer. Consequently, following the demonstration that thienotriazolodiazepine small molecules effectively inhibit BET, clinical trials were initiated. We thus discuss the mechanisms of action of various BET inhibitors and the prospects for their clinical use as cancer therapeutics.

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“…Overall, the drug was well-tolerated. However, owing to lack of detectable clinical activity the trial was close [ 111 ].…”

Section: Toxicities Of Clinically Used Bet Inhibitorsmentioning

confidence: 99%

Bromodomain and Extra-Terminal Motif Inhibitors: a Review of Preclinical and Clinical Advances in Cancer Therapy

et al. 2019

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“…We and others have shown that small molecule BET inhibitors reduce the growth of GBM and other brain tumors by competing with the BET-histone interaction, thereby reducing transcription of oncogenes important for GBM cell proliferation 11 , 12 , 14 , 15 . Further, BRD4 inhibition may restore sensitivity to certain kinase inhibitors 10 and BET inhibitors are well-tolerated in the clinic 16 , 17 .…”

Section: Introductionmentioning

confidence: 99%

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

Jermakowicz

Rybin

Suter

et al. 2021

Sci Rep

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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.

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“…Previous studies have demonstrated upregulation of several BET transcription factors in glioblastomas (59,60), and multiple pre-clinical studies have investigated the potential of BET inhibition as a single drug treatment for glioblastoma (61)(62)(63). However, while clinical trials with the BET inhibitor OTX015 demonstrated low toxicity at doses achieving biologically active levels, no detectable clinical benefits were found (64). This prompted approaches using drug combinatorial treatments (65) such as combining HDACi and BETi (66,67).…”

Section: Our Results Uncovered a Strong Correlation Between Bet Inhibmentioning

confidence: 99%

Improving drug discovery using image-based multiparametric analysis of epigenetic landscape

Farhy

Hariharan

Ylanko

et al. 2019

Preprint

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With the advent of automatic cell imaging and machine learning, high-content phenotypic screening has become the approach of choice for drug discovery because it can extract drug-specific multi-layered data, which could be compared to known profiles. In the field of epigenetics, such screening approaches have suffered from a lack of tools sensitive to selective epigenetic perturbations. Here we describe a novel approach, Microscopic Imaging of Epigenetic Landscapes (MIEL), which captures the nuclear staining patterns of epigenetic marks (e.g., acetylated and methylated histones) and employs machine learning to accurately distinguish between such patterns. We validated the fidelity and robustness of the MIEL platform across multiple cells lines using dose-response curves. We employed MIEL to uncover the mechanism by which bromodomain inhibitors synergize with temozolomidemediated killing of human glioblastoma lines. To explore alternative, non-cytotoxic, glioblastoma treatment, we screen the Prestwick chemical library and documented the power of MIEL platform to identify epigenetically active drugs and accurately rank them according to their ability to produce epigenetic and transcriptional alterations consistent with the induction of glioblastoma differentiation.

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Dose optimization of MK-8628 (OTX015), a small molecule inhibitor of bromodomain and extra-terminal (BET) proteins, in patients (pts) with recurrent glioblastoma (GB).

Cited by 18 publications

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Bromodomain and Extra-Terminal Motif Inhibitors: a Review of Preclinical and Clinical Advances in Cancer Therapy

Bromodomain and Extra-Terminal Motif Inhibitors: a Review of Preclinical and Clinical Advances in Cancer Therapy

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

Improving drug discovery using image-based multiparametric analysis of epigenetic landscape

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