Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

Hewings, David S.; Fedorov, O.; Filippakopoulos, P.; Martin, Sarah; Picaud, S.; Tumber, Anthony; Wells, Christopher; Olcina, Monica M.; Freeman, Katherine M.; Gill, Andrew B.; Ritchie, Alison J.; Sheppard, David W.; Russell, Angela J.; Hammond, Ester M.; Knapp, Stefan; Brennan, P.E.; Conway, Stuart J.

doi:10.1021/jm301588r

Cited by 124 publications

(108 citation statements)

References 38 publications

(169 reference statements)

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“…The residue was purified by chromatography on silica gel (5% MeOH in CH 2 Cl 2 ) to give 12 4-((2S*,4R*)-1-Acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic Acid (19). Method D was used to hydrolyze methyl 4-((2S*,4R*)-1-acetyl-2-methyl-4-(phenylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (18) 4-((2S*,4R*)-1-Acetyl-2-methyl-4-(p-tolylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic Acid (33). Method B was used to couple methyl 4-((2S*,4R*)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (57a) and 4-tolylboronic acid.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

et al. 2014

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Through their function as epigenetic readers of the histone code, the BET family of bromodomain-containing proteins regulate expression of multiple genes of therapeutic relevance, including those involved in tumor cell growth and inflammation. BET bromodomain inhibitors have profound antiproliferative and anti-inflammatory effects which translate into efficacy in oncology and inflammation models, and the first compounds have now progressed into clinical trials. The exciting biology of the BETs has led to great interest in the discovery of novel inhibitor classes. Here we describe the identification of a novel tetrahydroquinoline series through up-regulation of apolipoprotein A1 and the optimization into potent compounds active in murine models of septic shock and neuroblastoma. At the molecular level, these effects are produced by inhibition of BET bromodomains. X-ray crystallography reveals the interactions explaining the structure-activity relationships of binding. The resulting lead molecule, I-BET726, represents a new, potent, and selective class of tetrahydroquinoline-based BET inhibitors.

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Section: ■ Experimental Sectionmentioning

confidence: 99%

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

et al. 2014

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“…Many BET inhibitors chemically resemble thienodiazepines (such as JQ1, I-BET151, and OTX-015), although others have unrelated structures [59,60]. This current generation of molecules simultaneously inhibits all BET family members.…”

Section: Implications For Rational Design Of Bet Inhibitorsmentioning

confidence: 99%

Erythropoiesis provides a BRD's eye view of BET protein function

Stonestrom

Hsu

Werner

et al. 2016

Drug Discovery Today: Technologies

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Pharmacologic inhibitors of the bromodomain and extra-terminal motif (BET) protein family are in clinical trials for the treatment of hematologic malignancies, yet the functions of individual BET proteins remain largely uncharacterized. We review the molecular roles of BETs in the context of erythropoiesis. Studies in this lineage have provided valuable insights into their mechanisms of action, and helped define the individual and overlapping functions of BET protein family members BRD2, BRD3, and BRD4. These studies have important ramifications for our understanding of the molecular and physiologic roles of BET proteins, and provide a framework for elucidating some of the beneficial and adverse effects of pharmacologic inhibitors.

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“…12 There is growing evidence that the two bromodomains of BRD4 have different biological functions. 10, 12, 13 Despite several potent BET inhibitors reported in recent studies, 6, 7, 10, 14–17 there is still no small molecule inhibitor shown to be capable of differentiating between the two bromodomains within any individual BET protein. Developing such a selective inhibitor is a challenging task because of the extremely high sequence identity of these bromodomains, particularly at their acetyl-lysine binding pockets.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains

et al. 2013

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BRD4, characterized by two acetyl-lysine binding bromodomains and an extra-terminal (ET) domain, is a key chromatin organizer that directs gene activation in chromatin through transcription factor recruitment, enhancer assembly, and pause release of the RNA polymerase II complex for transcription elongation. BRD4 has been recently validated as a new epigenetic drug target for cancer and inflammation. Our current knowledge of the functional differences of the two bromodomains of BRD4, however, is limited, hindered by the lack of selective inhibitors. Here, we report our structure-guided development of diazobenzene-based small molecule inhibitors for the BRD4 bromodomains that have over 90% sequence identity at the acetyl-lysine binding site. Our lead compound MS436, through a set of water-mediated interactions, exhibits low nanomolar affinity (estimated Ki of 30–50 nM) with preference for the first bromodomain over the second. We demonstrated that MS436 effectively inhibits BRD4 activity in NF-κB-directed production of nitric oxide and pro-inflammatory cytokine interleukin-6 in murine macrophages. MS436 represents a new class of bromodomain inhibitors and will facilitate further investigation of the biological functions of the two bromodomains of BRD4 in gene expression.

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Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

Cited by 124 publications

References 38 publications

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

The Discovery of I-BET726 (GSK1324726A), a Potent Tetrahydroquinoline ApoA1 Up-Regulator and Selective BET Bromodomain Inhibitor

Erythropoiesis provides a BRD's eye view of BET protein function

Structure-Guided Design of Potent Diazobenzene Inhibitors for the BET Bromodomains

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