15 research outputs found

    Fragment-Based Discovery of Bromodomain Inhibitors Part 1: Inhibitor Binding Modes and Implications for Lead Discovery

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    Bromodomain-containing proteins are key epigenetic regulators of gene transcription and readers of the histone code. However, the therapeutic benefits of modulating this target class are largely unexplored due to the lack of suitable chemical probes. This article describes the generation of lead molecules for the BET bromodomains through screening a fragment set chosen using structural insights and computational approaches. Analysis of 40 BRD2/fragment X-ray complexes highlights both shared and disparate interaction features that may be exploited for affinity and selectivity. Six representative crystal structures are then exemplified in detail. Two of the fragments are completely new bromodomain chemotypes, and three have never before been crystallized in a bromodomain, so our results significantly extend the limited public knowledge-base of crystallographic small molecule/bromodomain interactions. Certain fragments (including paracetamol) bind in a consistent mode to different bromodomains such as CREBBP, suggesting their potential to act as generic bromodomain templates. An important implication is that the bromodomains are not only a phylogenetic family but also a system in which chemical and structural knowledge of one bromodomain gives insights transferrable to others

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

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    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

    Fragment-Based Discovery of Bromodomain Inhibitors Part 2: Optimization of Phenylisoxazole Sulfonamides

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    Bromodomains are epigenetic reader modules that regulate gene transcription through their recognition of acetyl-lysine modified histone tails. Inhibitors of this proteinā€“protein interaction have the potential to modulate multiple diseases as demonstrated by the profound anti-inflammatory and antiproliferative effects of a recently disclosed class of BET compounds. While these compounds were discovered using phenotypic assays, here we present a highly efficient alternative approach to find new chemical templates, exploiting the abundant structural knowledge that exists for this target class. A phenyl dimethyl isoxazole chemotype resulting from a focused fragment screen has been rapidly optimized through structure-based design, leading to a sulfonamide series showing anti-inflammatory activity in cellular assays. This proof-of-principle experiment demonstrates the tractability of the BET family and bromodomain target class to fragment-based hit discovery and structure-based lead optimization

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

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    The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomainsī—øBRD2, BRD3, BRD4, and BRDTī—øeach 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

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

    No full text
    The bromodomain and extra-terminal domain (BET) family of proteins bind acetylated lysine residues on histone proteins. The four BET bromodomainsī—øBRD2, BRD3, BRD4, and BRDTī—øeach 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

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

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    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 structureā€“activity relationship (SAR) of the first potent, selective series of inhibitors of the BRPF1 bromodomain

    Structure-Based Optimization of Naphthyridones into Potent ATAD2 Bromodomain Inhibitors

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    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

    Discovery of Epigenetic Regulator Iā€‘BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

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    The bromo and extra C-terminal domain (BET) family of bromodomains are involved in binding epigenetic marks on histone proteins, more specifically acetylated lysine residues. This paper describes the discovery and structureā€“activity relationships (SAR) of potent benzodiazepine inhibitors that disrupt the function of the BET family of bromodomains (BRD2, BRD3, and BRD4). This work has yielded a potent, selective compound I-BET762 that is now under evaluation in a phase I/II clinical trial for nuclear protein in testis (NUT) midline carcinoma and other cancers

    Fragment-Based Discovery of Low-Micromolar ATAD2 Bromodomain Inhibitors

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    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

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

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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 structureā€“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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