Publications by authors named "Paul Bamborough"

62 Publications

Template-Hopping Approach Leads to Potent, Selective, and Highly Soluble Bromo and Extraterminal Domain (BET) Second Bromodomain (BD2) Inhibitors.

J Med Chem 2021 Mar 4;64(6):3249-3281. Epub 2021 Mar 4.

Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.

A number of reports have recently been published describing the discovery and optimization of bromo and extraterminal inhibitors which are selective for the second bromodomain (BD2); these include our own work toward GSK046 () and GSK620 (). This paper describes our approach to mitigating the genotoxicity risk of GSK046 by replacement of the acetamide functionality with a heterocyclic ring. This was followed by a template-hopping and hybridization approach, guided by structure-based drug design, to incorporate learnings from other BD2-selective series, optimize the vector for the amide region, and explore the ZA cleft, leading to the identification of potent, selective, and bioavailable compounds (GSK452), (GSK737), and (GSK217).
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http://dx.doi.org/10.1021/acs.jmedchem.0c02156DOI Listing
March 2021

GSK973 Is an Inhibitor of the Second Bromodomains (BD2s) of the Bromodomain and Extra-Terminal (BET) Family.

ACS Med Chem Lett 2020 Aug 6;11(8):1581-1587. Epub 2020 Jul 6.

Epigenetics Discovery Performance Unit and Platform Technology and Science, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

Pan-BET inhibitors have shown profound efficacy in a number of in vivo preclinical models and have entered the clinic in oncology trials where adverse events have been reported. These inhibitors interact equipotently with the eight bromodomains of the BET family of proteins. To better understand the contribution of each domain to their efficacy and to improve from their safety profile, selective inhibitors are required. This Letter discloses the profile of GSK973, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive preclinical in vitro and in vivo characterization.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429977PMC
August 2020

Structure-Based Design of a Bromodomain and Extraterminal Domain (BET) Inhibitor Selective for the N-Terminal Bromodomains That Retains an Anti-inflammatory and Antiproliferative Phenotype.

J Med Chem 2020 09 3;63(17):9020-9044. Epub 2020 Aug 3.

GSK, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.

The bromodomain and extraterminal domain (BET) family of epigenetic regulators comprises four proteins (BRD2, BRD3, BRD4, BRDT), each containing tandem bromodomains. To date, small molecule inhibitors of these proteins typically bind all eight bromodomains of the family with similar affinity, resulting in a diverse range of biological effects. To enable further understanding of the broad phenotype characteristic of pan-BET inhibition, the development of inhibitors selective for individual, or sets of, bromodomains within the family is required. In this regard, we report the discovery of a potent probe molecule possessing up to 150-fold selectivity for the N-terminal bromodomains (BD1s) over the C-terminal bromodomains (BD2s) of the BETs. Guided by structural information, a specific amino acid difference between BD1 and BD2 domains was targeted for selective interaction with chemical functionality appended to the previously developed I-BET151 scaffold. Data presented herein demonstrate that selective inhibition of BD1 domains is sufficient to drive anti-inflammatory and antiproliferative effects.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00566DOI Listing
September 2020

A Photoaffinity-Based Fragment-Screening Platform for Efficient Identification of Protein Ligands.

Angew Chem Int Ed Engl 2020 11 7;59(47):21096-21105. Epub 2020 Sep 7.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, UK.

Advances in genomic analyses enable the identification of new proteins that are associated with disease. To validate these targets, tool molecules are required to demonstrate that a ligand can have a disease-modifying effect. Currently, as tools are reported for only a fraction of the proteome, platforms for ligand discovery are essential to leverage insights from genomic analyses. Fragment screening offers an efficient approach to explore chemical space. Presented here is a fragment-screening platform, termed PhABits (PhotoAffinity Bits), which utilizes a library of photoreactive fragments to covalently capture fragment-protein interactions. Hits can be profiled to determine potency and the site of crosslinking, and subsequently developed as reporters in a competitive displacement assay to identify novel hit matter. The PhABit platform is envisioned to be widely applicable to novel protein targets, identifying starting points in the development of therapeutics.
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http://dx.doi.org/10.1002/anie.202008361DOI Listing
November 2020

The Optimization of a Novel, Weak Bromo and Extra Terminal Domain (BET) Bromodomain Fragment Ligand to a Potent and Selective Second Bromodomain (BD2) Inhibitor.

J Med Chem 2020 09 30;63(17):9093-9126. Epub 2020 Aug 30.

IVIVT Cellzome, Platform Technology and Science, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

The profound efficacy, yet associated toxicity of pan-BET inhibitors is well documented. The possibility of an ameliorated safety profile driven by significantly selective (>100-fold) inhibition of a subset of the eight bromodomains is enticing, but challenging given the close homology. Herein, we describe the X-ray crystal structure-directed optimization of a novel weak fragment ligand with a pan-second bromodomain (BD2) bias, to potent and highly BD2 selective inhibitors. A template hopping approach, enabled by our parallel research into an orthogonal template (, GSK046), was the basis for the high selectivity observed. This culminated in two tool molecules, (GSK620) and (GSK549), which showed an anti-inflammatory phenotype in human whole blood, confirming their cellular target engagement. Excellent broad selectivity, developability, and in vivo oral pharmacokinetics characterize these tools, which we hope will be of broad utility to the field of epigenetics research.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00796DOI Listing
September 2020

Design and Synthesis of a Highly Selective and -Capable Inhibitor of the Second Bromodomain of the Bromodomain and Extra Terminal Domain Family of Proteins.

J Med Chem 2020 09 20;63(17):9070-9092. Epub 2020 Aug 20.

Epigenetics Discovery Performance Unit, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire SG1 2NY, U.K.

Pan-bromodomain and extra terminal domain (BET) inhibitors interact equipotently with the eight bromodomains of the BET family of proteins and have shown profound efficacy in a number of phenotypic assays and pre-clinical models in inflammation or oncology. A number of these inhibitors have progressed to the clinic where pharmacology-driven adverse events have been reported. To better understand the contribution of each domain to their efficacy and improve their safety profile, selective inhibitors are required. This article discloses the profile of GSK046, also known as iBET-BD2, a highly selective inhibitor of the second bromodomains of the BET proteins that has undergone extensive pre-clinical and characterization.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00605DOI Listing
September 2020

GSK789: A Selective Inhibitor of the First Bromodomains (BD1) of the Bromo and Extra Terminal Domain (BET) Proteins.

J Med Chem 2020 09 4;63(17):9045-9069. Epub 2020 Aug 4.

Molecular Discovery Research, GlaxoSmithKline, Cellzome GmbH, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

Pan-bromodomain and extra terminal (BET) inhibitors interact equipotently with all eight bromodomains of the BET family of proteins. They have shown profound efficacy in vitro and in vivo in oncology and immunomodulatory models, and a number of them are currently in clinical trials where significant safety signals have been reported. It is therefore important to understand the functional contribution of each bromodomain to assess the opportunity to tease apart efficacy and toxicity. This article discloses the in vitro and cellular activity profiles of GSK789, a potent, cell-permeable, and highly selective inhibitor of the first bromodomains of the BET family.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00614DOI Listing
September 2020

Application of Atypical Acetyl-lysine Methyl Mimetics in the Development of Selective Inhibitors of the Bromodomain-Containing Protein 7 (BRD7)/Bromodomain-Containing Protein 9 (BRD9) Bromodomains.

J Med Chem 2020 06 29;63(11):5816-5840. Epub 2020 May 29.

GlaxoSmithKline R&D, Stevenage SG1 2NY, Hertfordshire, United Kingdom.

Non-BET bromodomain-containing proteins have become attractive targets for the development of novel therapeutics targeting epigenetic pathways. To help facilitate the target validation of this class of proteins, structurally diverse small-molecule ligands and methodologies to produce selective inhibitors in a predictable fashion are in high demand. Herein, we report the development and application of atypical acetyl-lysine (KAc) methyl mimetics to take advantage of the differential stability of conserved water molecules in the bromodomain binding site. Discovery of the -butyl group as an atypical KAc methyl mimetic allowed generation of (GSK6776) as a soluble, permeable, and selective BRD7/9 inhibitor from a pyridazinone template. The -butyl group was then used to enhance the bromodomain selectivity of an existing BRD9 inhibitor and to transform pan-bromodomain inhibitors into BRD7/9 selective compounds. Finally, a solvent-exposed vector was defined from the pyridazinone template to enable bifunctional molecule synthesis, and affinity enrichment chemoproteomic experiments were used to confirm several of the endogenous protein partners of BRD7 and BRD9, which form part of the chromatin remodeling PBAF and BAF complexes, respectively.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00075DOI Listing
June 2020

CDK12 inhibition reduces abnormalities in cells from patients with myotonic dystrophy and in a mouse model.

Sci Transl Med 2020 04;12(541)

School of Life Sciences, University of Nottingham, Queen's Medical Centre, Nottingham NG7 2UH, UK.

Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase () gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSA mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.
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http://dx.doi.org/10.1126/scitranslmed.aaz2415DOI Listing
April 2020

Optimization of Potent ATAD2 and CECR2 Bromodomain Inhibitors with an Atypical Binding Mode.

J Med Chem 2020 05 6;63(10):5212-5241. Epub 2020 May 6.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street, Glasgow G1 1XL, United Kingdom.

Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimization of a series of phenyl sulfonamides that exhibit a novel mode of binding to non-bromodomain and extra terminal domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule, we report its divergent optimization toward the ATPase family AAA domain containing 2 (ATAD2) and cat eye syndrome chromosome region, candidate 2 (CECR2) domains. This work concludes with the identification of (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00021DOI Listing
May 2020

Selective targeting of BD1 and BD2 of the BET proteins in cancer and immunoinflammation.

Science 2020 04 19;368(6489):387-394. Epub 2020 Mar 19.

Cellzome GmbH, Functional Genomics R&D, GlaxoSmithKline, Heidelberg, Germany.

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.
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http://dx.doi.org/10.1126/science.aaz8455DOI Listing
April 2020

Discovery of a Bromodomain and Extraterminal Inhibitor with a Low Predicted Human Dose through Synergistic Use of Encoded Library Technology and Fragment Screening.

J Med Chem 2020 01 6;63(2):714-746. Epub 2020 Jan 6.

GSK , Gunnels Wood Road , Stevenage , Hertfordshire SG1 2NY , U.K.

The bromodomain and extraterminal (BET) family of bromodomain-containing proteins are important regulators of the epigenome through their ability to recognize -acetyl lysine (KAc) post-translational modifications on histone tails. These interactions have been implicated in various disease states and, consequently, disruption of BET-KAc binding has emerged as an attractive therapeutic strategy with a number of small molecule inhibitors now under investigation in the clinic. However, until the utility of these advanced candidates is fully assessed by these trials, there remains scope for the discovery of inhibitors from new chemotypes with alternative physicochemical, pharmacokinetic, and pharmacodynamic profiles. Herein, we describe the discovery of a candidate-quality dimethylpyridone benzimidazole compound which originated from the hybridization of a dimethylphenol benzimidazole series, identified using encoded library technology, with an -methyl pyridone series identified through fragment screening. Optimization via structure- and property-based design led to I-BET469, which possesses favorable oral pharmacokinetic properties, displays activity in vivo, and is projected to have a low human efficacious dose.
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http://dx.doi.org/10.1021/acs.jmedchem.9b01670DOI Listing
January 2020

A Qualified Success: Discovery of a New Series of ATAD2 Bromodomain Inhibitors with a Novel Binding Mode Using High-Throughput Screening and Hit Qualification.

J Med Chem 2019 08 9;62(16):7506-7525. Epub 2019 Aug 9.

GlaxoSmithKline Tres Cantos , 28760 Tres Cantos , Madrid , Spain.

The bromodomain of ATAD2 has proved to be one of the least-tractable proteins within this target class. Here, we describe the discovery of a new class of inhibitors by high-throughput screening and show how the difficulties encountered in establishing a screening triage capable of finding progressible hits were overcome by data-driven optimization. Despite the prevalence of nonspecific hits and an exceptionally low progressible hit rate (0.001%), our optimized hit qualification strategy employing orthogonal biophysical methods enabled us to identify a single active series. The compounds have a novel ATAD2 binding mode with noncanonical features including the displacement of all conserved water molecules within the active site and a halogen-bonding interaction. In addition to reporting this new series and preliminary structure-activity relationship, we demonstrate the value of diversity screening to complement the knowledge-based approach used in our previous ATAD2 work. We also exemplify tactics that can increase the chance of success when seeking new chemical starting points for novel and less-tractable targets.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00673DOI Listing
August 2019

3,5-Disubstituted-indole-7-carboxamides as IKKβ Inhibitors: Optimization of Oral Activity via the C3 Substituent.

ACS Med Chem Lett 2018 Dec 30;9(12):1164-1169. Epub 2018 Oct 30.

GlaxoSmithKline Inc., 709 Swedeland Road, King of Prussia Pennsylvania 19406, United States.

IκB kinase β (IKKβ or IKK2) is a key regulator of nuclear factor kappa B (NF-κB) and has received attention as a therapeutic target. Herein we report on the optimization of a series of 3,5-disubstituted-indole-7-carboxamides for oral activity. In doing so, we focused attention on potency, ligand efficiency (LE), and physicochemical properties and have identified compounds and ()- as having robust in vivo activity.
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http://dx.doi.org/10.1021/acsmedchemlett.8b00291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6295857PMC
December 2018

Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.

J Med Chem 2018 09 18;61(18):8321-8336. Epub 2018 Sep 18.

Molecular Discovery Research, Cellzome GmbH , GlaxoSmithKline , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.
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http://dx.doi.org/10.1021/acs.jmedchem.8b00862DOI Listing
September 2018

Discovery of Tetrahydroquinoxalines as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the Second Bromodomain.

J Med Chem 2018 05 3;61(10):4317-4334. Epub 2018 May 3.

WestCHEM, Department of Pure and Applied Chemistry , University of Strathclyde, Thomas Graham Building , 295 Cathedral Street , Glasgow , G1 1XL , U.K.

The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomains-BRD2, BRD3, BRD4, and BRDT-each contain two bromodomain modules. BET bromodomain inhibition is a potential therapy for various cancers and immunoinflammatory diseases, but few reported inhibitors show selectivity within the BET family. Inhibitors with selectivity for the first or second bromodomain are desired to aid investigation of the biological function of these domains. Focused library screening identified a series of tetrahydroquinoxalines with selectivity for the second bromodomains of the BET family (BD2). Structure-guided optimization of the template improved potency, selectivity, and physicochemical properties, culminating in potent BET inhibitors with BD2 selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01666DOI Listing
May 2018

The Discovery of Novel Antimalarial Aminoxadiazoles as a Promising Nonendoperoxide Scaffold.

J Med Chem 2017 08 14;60(16):6880-6896. Epub 2017 Aug 14.

Tres Cantos, Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2, 28760 Tres Cantos, Madrid, Spain.

Since the appearance of resistance to the current front-line antimalarial treatments, ACTs (artemisinin combination therapies), the discovery of novel chemical entities to treat the disease is recognized as a major global health priority. From the GSK antimalarial set, we identified an aminoxadiazole with an antiparasitic profile comparable with artemisinin (1), with no cross-resistance in a resistant strains panel and a potential new mode of action. A medicinal chemistry program allowed delivery of compounds such as 19 with high solubility in aqueous media, an acceptable toxicological profile, and oral efficacy. Further evaluation of the lead compounds showed that in vivo genotoxic degradants might be generated. The compounds generated during this medicinal chemistry program and others from the GSK collection were used to build a pharmacophore model which could be used in the virtual screening of compound collections and potentially identify new chemotypes that could deliver the same antiparasitic profile.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01441DOI Listing
August 2017

Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors.

Bioorg Med Chem Lett 2017 09 21;27(17):4034-4038. Epub 2017 Jul 21.

Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China. Electronic address:

Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.
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http://dx.doi.org/10.1016/j.bmcl.2017.07.052DOI Listing
September 2017

Rapid and Reliable Binding Affinity Prediction of Bromodomain Inhibitors: A Computational Study.

J Chem Theory Comput 2017 Feb 18;13(2):784-795. Epub 2017 Jan 18.

Centre for Computational Science, Department of Chemistry, University College London , London WC1H 0AJ, United Kingdom.

Binding free energies of bromodomain inhibitors are calculated with recently formulated approaches, namely ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling). A set of compounds is provided by GlaxoSmithKline, which represents a range of chemical functionality and binding affinities. The predicted binding free energies exhibit a good Spearman correlation of 0.78 with the experimental data from the 3-trajectory ESMACS, and an excellent correlation of 0.92 from the TIES approach where applicable. Given access to suitable high end computing resources and a high degree of automation, we can compute individual binding affinities in a few hours with precisions no greater than 0.2 kcal/mol for TIES, and no larger than 0.34 and 1.71 kcal/mol for the 1- and 3-trajectory ESMACS approaches.
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http://dx.doi.org/10.1021/acs.jctc.6b00794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5312866PMC
February 2017

Discovery of a Potent, Cell Penetrant, and Selective p300/CBP-Associated Factor (PCAF)/General Control Nonderepressible 5 (GCN5) Bromodomain Chemical Probe.

J Med Chem 2017 01 9;60(2):695-709. Epub 2017 Jan 9.

WestCHEM, Department of Pure and Applied Chemistry, University of Strathclyde , Thomas Graham Building, 295 Cathedral Street, Glasgow, G1 1XL, United Kingdom.

p300/CREB binding protein associated factor (PCAF/KAT2B) and general control nonderepressible 5 (GCN5/KAT2A) are multidomain proteins that have been implicated in retroviral infection, inflammation pathways, and cancer development. However, outside of viral replication, little is known about the dependence of these effects on the C-terminal bromodomain. Herein, we report GSK4027 as a chemical probe for the PCAF/GCN5 bromodomain, together with GSK4028 as an enantiomeric negative control. The probe was optimized from a weakly potent, nonselective pyridazinone hit to deliver high potency for the PCAF/GCN5 bromodomain, high solubility, cellular target engagement, and ≥18000-fold selectivity over the BET family, together with ≥70-fold selectivity over the wider bromodomain families.
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http://dx.doi.org/10.1021/acs.jmedchem.6b01566DOI Listing
January 2017

A Chemical Probe for the ATAD2 Bromodomain.

Angew Chem Int Ed Engl 2016 09 17;55(38):11382-6. Epub 2016 Aug 17.

GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, UK.

ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of that target class. Starting from a potent lead, permeability and selectivity were improved through a dual approach: 1) using CF2 as a sulfone bio-isostere to exploit the unique properties of fluorine, and 2) using 1,3-interactions to control the conformation of a piperidine ring. This resulted in the first reported low-nanomolar, selective and cell permeable chemical probe for ATAD2.
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http://dx.doi.org/10.1002/anie.201603928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314595PMC
September 2016

GSK6853, a Chemical Probe for Inhibition of the BRPF1 Bromodomain.

ACS Med Chem Lett 2016 Jun 9;7(6):552-7. Epub 2016 May 9.

Epinova Discovery Performance Unit, Quantitative Pharmacology, Experimental Medicine Unit, Flexible Discovery Unit, and Platform Technology and Science, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

The BRPF (Bromodomain and PHD Finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. A selective benzimidazolone BRPF1 inhibitor showing micromolar activity in a cellular target engagement assay was recently described. Herein, we report the optimization of this series leading to the identification of a superior BRPF1 inhibitor suitable for in vivo studies.
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http://dx.doi.org/10.1021/acsmedchemlett.6b00092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4904261PMC
June 2016

Comprehensive characterization of the Published Kinase Inhibitor Set.

Nat Biotechnol 2016 Jan 26;34(1):95-103. Epub 2015 Oct 26.

Chemical Sciences, GlaxoSmithKline, Research Triangle Park, North Carolina, USA.

Despite the success of protein kinase inhibitors as approved therapeutics, drug discovery has focused on a small subset of kinase targets. Here we provide a thorough characterization of the Published Kinase Inhibitor Set (PKIS), a set of 367 small-molecule ATP-competitive kinase inhibitors that was recently made freely available with the aim of expanding research in this field and as an experiment in open-source target validation. We screen the set in activity assays with 224 recombinant kinases and 24 G protein-coupled receptors and in cellular assays of cancer cell proliferation and angiogenesis. We identify chemical starting points for designing new chemical probes of orphan kinases and illustrate the utility of these leads by developing a selective inhibitor for the previously untargeted kinases LOK and SLK. Our cellular screens reveal compounds that modulate cancer cell growth and angiogenesis in vitro. These reagents and associated data illustrate an efficient way forward to increasing understanding of the historically untargeted kinome.
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http://dx.doi.org/10.1038/nbt.3374DOI Listing
January 2016

Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Aug 31;58(15):6151-78. Epub 2015 Jul 31.

∥Cellzome GmbH, Molecular Discovery Research, GlaxoSmithKline, Meyerhofstrasse 1, 69117 Heidelberg, Germany.

ATAD2 is a bromodomain-containing protein whose overexpression is linked to poor outcomes in a number of different cancer types. To date, no potent and selective inhibitors of the bromodomain have been reported. This article describes the structure-based optimization of a series of naphthyridones from micromolar leads with no selectivity over the BET bromodomains to inhibitors with sub-100 nM ATAD2 potency and 100-fold BET selectivity.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00773DOI Listing
August 2015

Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors.

J Med Chem 2015 Jul 9;58(14):5649-73. Epub 2015 Jul 9.

∥Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline, Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom.

Overexpression of ATAD2 (ATPase family, AAA domain containing 2) has been linked to disease severity and progression in a wide range of cancers, and is implicated in the regulation of several drivers of cancer growth. Little is known of the dependence of these effects upon the ATAD2 bromodomain, which has been categorized as among the least tractable of its class. The absence of any potent, selective inhibitors limits clear understanding of the therapeutic potential of the bromodomain. Here, we describe the discovery of a hit from a fragment-based targeted array. Optimization of this produced the first known micromolar inhibitors of the ATAD2 bromodomain.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00772DOI Listing
July 2015

Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition.

J Med Chem 2016 Feb 30;59(4):1425-39. Epub 2015 Apr 30.

Epinova Discovery Performance Unit, GlaxoSmithKline R&D , Stevenage, Hertfordshire SG1 2NY, U.K.

Acetylation of histone lysine residues is one of the most well-studied post-translational modifications of chromatin, selectively recognized by bromodomain "reader" modules. Inhibitors of the bromodomain and extra terminal domain (BET) family of bromodomains have shown profound anticancer and anti-inflammatory properties, generating much interest in targeting other bromodomain-containing proteins for disease treatment. Herein, we report the discovery of I-BRD9, the first selective cellular chemical probe for bromodomain-containing protein 9 (BRD9). I-BRD9 was identified through structure-based design, leading to greater than 700-fold selectivity over the BET family and 200-fold over the highly homologous bromodomain-containing protein 7 (BRD7). I-BRD9 was used to identify genes regulated by BRD9 in Kasumi-1 cells involved in oncology and immune response pathways and to the best of our knowledge, represents the first selective tool compound available to elucidate the cellular phenotype of BRD9 bromodomain inhibition.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354103PMC
February 2016

Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B.

J Med Chem 2016 Feb 6;59(4):1410-24. Epub 2015 Apr 6.

Department of Chemical Biology, GlaxoSmithKline , Research Triangle Park, 5 Moore Drive, Research Triangle Park, North Carolina 27709-3398, United States.

Bromodomains are acetyl-lysine specific protein interaction domains that have recently emerged as a new target class for the development of inhibitors that modulate gene transcription. The two closely related bromodomain containing proteins BAZ2A and BAZ2B constitute the central scaffolding protein of the nucleolar remodeling complex (NoRC) that regulates the expression of noncoding RNAs. However, BAZ2 bromodomains have low predicted druggability and so far no selective inhibitors have been published. Here we report the development of GSK2801, a potent, selective and cell active acetyl-lysine competitive inhibitor of BAZ2A and BAZ2B bromodomains as well as the inactive control compound GSK8573. GSK2801 binds to BAZ2 bromodomains with dissociation constants (KD) of 136 and 257 nM for BAZ2B and BAZ2A, respectively. Crystal structures demonstrated a canonical acetyl-lysine competitive binding mode. Cellular activity was demonstrated using fluorescent recovery after photobleaching (FRAP) monitoring displacement of GFP-BAZ2A from acetylated chromatin. A pharmacokinetic study in mice showed that GSK2801 had reasonable in vivo exposure after oral dosing, with modest clearance and reasonable plasma stability. Thus, GSK2801 represents a versatile tool compound for cellular and in vivo studies to understand the role of BAZ2 bromodomains in chromatin biology.
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http://dx.doi.org/10.1021/acs.jmedchem.5b00209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770311PMC
February 2016

1,3-Dimethyl Benzimidazolones Are Potent, Selective Inhibitors of the BRPF1 Bromodomain.

ACS Med Chem Lett 2014 Nov 10;5(11):1190-5. Epub 2014 Sep 10.

Epinova Discovery Performance Unit and Molecular Discovery Research, GlaxoSmithKline , Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.

The BRPF (bromodomain and PHD finger-containing) protein family are important scaffolding proteins for assembly of MYST histone acetyltransferase complexes. Here, we report the discovery, binding mode, and structure-activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain.
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http://dx.doi.org/10.1021/ml5002932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4233354PMC
November 2014

The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor.

J Med Chem 2014 Oct 24;57(19):8111-31. Epub 2014 Sep 24.

Candidate Discovery, ‡Discovery Biology, §DMPK, GlaxoSmithKline Les Ulis, Centre de Recherches François Hyafil, GlaxoSmithKline R&D , 25 Avenue du Québec, 91140 Villebon-sur-Yvette, France.

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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http://dx.doi.org/10.1021/jm5010539DOI Listing
October 2014