BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

Chen, Lijia; Yap, Jeremy L.; Yoshioka, Makoto; Lanning, Maryanna E.; Fountain, Rachel N.; Raje, Mithun; Scheenstra, Jacob A.; Strovel, Jeffrey; Fletcher, Steven

doi:10.1021/acsmedchemlett.5b00084

Cited by 78 publications

(94 citation statements)

References 28 publications

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“…Soon after, two new studies (64, 65) identified more than a dozen kinase inhibitors that possess cross-reactivity towards BRD4 with nanomolar potencies, including the JAK2 inhibitor TG101209 and the PLK1 inhibitor BI2536 which is in Phase I/II Clinical trials for acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). This finding has triggered the development of more potent dual BET/PLK1 inhibitors using a structure–activity relationship (SAR) study (66). Notably, LY94002 which has been routinely used to block PI3K activity was also recently shown to interact with BRD2–4 (67).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue

Στρατικόπουλος

Parsons

2016

Clinical Cancer Research

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The phosphoinositide 3-kinase (PI3K) signaling pathway is a complex and tightly regulated network that is critical for many physiological processes such as cell growth, proliferation, metabolism and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extra-terminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT and ER pathways suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance clinical efficacy of PI3K inhibitors.

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Section: Clinical-translational Advancesmentioning

confidence: 99%

Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue

Στρατικόπουλος

Parsons

2016

Clinical Cancer Research

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“…While previous studies of BET inhibitors have used cellular viability assays as a high‐throughput surrogate for cellular activity, this is less feasible for a recently reported class of compounds that can inhibit both BET proteins and selected kinase signaling proteins . This includes BI2536 that possesses dual activity against BET proteins and PLK1.…”

Section: Figurementioning

confidence: 99%

“…Included in this set are four compounds recently described by Chen et al. in similar in vitro BRD4 and PLK1 activity and cell viability assays ( 1/39 q , 3/39 p , 5/39 b , 7/39 a ) . Our data here largely corresponds with previously reported activity trends for these compounds.…”

Section: Figurementioning

confidence: 99%

“…While previouss tudies of BET inhibitors have used cellular viability assays as ah igh-throughput surrogate for cellular activity,t his is less feasible for ar ecently reported class of compounds that can inhibit both BET proteins and selected kinase signaling proteins. [13][14][15] This includes BI2536 that possesses dual activity against BET proteins and PLK1. Each of thesea ctivities likely contributes to decreased cellular viability.T herefore, to assess the cellular inhibition of BRD4 in ah ighthroughput fashion, we tested BI2536 and ac ollection of structurally analogous derivatives predicted to be JQ1-competitive in the BET-BRET assay.T hese compounds included derivatives of BI2536, with varying substituents on the dihydropteridinone core and off of the central aryl ring.…”

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Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET‐BRET

et al. 2016

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Evaluating the engagement of a small molecule ligand with a protein target in cells provides useful information for chemical probe optimization and pharmaceutical development. While several techniques exist that can be performed in a low-throughput manner, systematic evaluation of large compound libraries remains a challenge. In-cell engagement measurements are especially useful when evaluating compound classes suspected to target multiple cellular factors. In this study we used a bioluminescent resonant energy transfer assay to assess bromodomain engagement by a compound series containing bromodomain- and kinase-biasing polypharmacophores based on the known dual BRD4 bromodomain/PLK1 kinase inhibitor BI2536. With this assay, we discovered several novel agents with bromodomain-selective specificity profiles and cellular activity. Thus, this platform aids in distinguishing molecules whose cellular activity is difficult to assess due to polypharmacologic effects.

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“…We found that MYC was downregulated and AKT3 was upregulated in these cells. BI 2536 and BI 6727 are dual inhibitors of both PLK1 and bromodomain containing 4 (BRD4) . The high concentration of BI 2536 represses MYC transcription by inhibiting BRD4, and AKT‐mediated phosphorylation of GSK‐3β at Ser‐9 represses GSK‐3β activity .…”

Section: Discussionmentioning

confidence: 99%

Effect of AKT3 expression on MYC‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells

et al. 2016

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Polo‐like kinase (PLK) is a cell‐cycle regulator that is overexpressed in several cancer cell types. Polo‐like kinase is considered a novel target for cancer therapies, and several PLK inhibitors (PLKis), including BI 2536, BI 6727, and GSK461364, have been developed. In this study, we established five BI 2536‐resistant cell lines from human colorectal cancer HCT 116 cells, to explore the resistance mechanism and identify predictable biomarkers of PLKis. We showed that PLKi‐induced caspase‐8 activation was attenuated in the BI 2536‐resistant cell lines. We also showed that the expression of P‐glycoprotein (P‐GP) and AKT3 was upregulated, whereas that of MYC was downregulated in some BI 2536‐resistant cell lines. Expression of P‐GP conferred resistance to PLKis, and PLKi‐induced apoptosis was dependent on MYC and caspase‐8 in HCT 116 cells. We also showed for the first time that AKT3 suppressed BI 6727‐induced caspase‐8 activation and conferred resistance to PLKis. Collectively, these results indicate that MYC, caspase‐8, P‐GP, and AKT3 play critical roles in PLKi‐induced apoptosis. Therefore, they are candidate biomarkers of the pharmacological efficacy of PLKis.

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BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

Cited by 78 publications

References 28 publications

Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue

Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue

Assessment of Bromodomain Target Engagement by a Series of BI2536 Analogues with Miniaturized BET‐BRET

Effect of AKT3 expression on MYC‐ and caspase‐8‐dependent apoptosis caused by polo‐like kinase inhibitors in HCT 116 cells

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