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Fragments in Bromodomain Drug Discovery

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Fragments in Bromodomain Drug Discovery MedChemComm Fragments in Bromodomain Drug Discovery Journal: MedChemComm Manuscript ID: MD-REV-05-2015-000209.R1 Article Type: Review Article Date Submitted by the Author: 30-Jun-2015 Complete List of Authors: Bamborough, P; GlaxoSmithKline, Chung, Chun-wa; GlaxoSmithKline, Computational and Structural Chemistry Page 1 of 18Journal Name MedChemComm Dynamic Article Links ► Cite this: DOI: 10.1039/c0xx00000x www.rsc.org/xxxxxx ARTICLE TYPE Fragments in Bromodomain Drug Discovery Paul Bamborough*a and Chun-wa Chung a Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x 5 Fragment-based approaches have been successfully applied to the discovery and optimisation of ligands for a wide range of targets. These concepts are proving valuable for bromodomain-containing proteins, an emerging family of epigenetic regulators. This review gives examples in which fragment-based drug discovery concepts are helping to find and optimise bromodomain inhibitors, with early successes against the BET subfamily now extending to other members of the target class. 10 Introduction bromodomain modules is thought to be to recruit additional effectors to sites of histone acetylation around activated genes, so Following the discovery that small-molecule binding to the acting as readers of the “histone code”. 9-12 acetyl-lysine (KAc) pocket of bromodomain modules can block 50 Bromodomains form four-helical bundles, with the peptide- the recognition of their acetylated partner proteins, binding site located at the end furthest from the two termini bromodomains have become a very active target class for drug (Figure 3). Most bromodomains recognise their targets by means 15 discovery. Excitement has been fuelled by their potential of multiple interactions within and outside their acetyl-lysine tractability and the prospect of finding novel epigenetic sites. The acetylated lysine itself is bound by a cluster of mechanisms to tackle complex diseases such as cancer and 55 conserved residues, in particular an asparagine and tyrosine inflammation. Inhibitors of the BET (Bromodomain and Extra structural motif, and associated conserved water molecules Terminal domain) family of tandem bromodomain-containing (Figure 3). In contrast to these “typical” bromodomains, some 20 proteins (BRD2, BRD3, BRD4 and BRDT) exhibit wide-ranging lack these conserved residues (Figure 2), and it is unclear whether biological effects and therapeutic potential.1,2 Indeed, the first they still bind to acetylated lysine peptides, have alternative BET inhibitors (including 1-4, Figure 1) were identified through 60 substrate recognition specificity, or are “pseudo-bromodomains” their effects in cellular systems.3-6 For example, 1 was found in without binding competency. an ApoA1 upregulator reporter assay while seeking leads for 25 atherosclerosis. The application of chemoproteomics, biophysics Cl Cl and crystallography proved that its mode of action was histone- competitive bromodomain binding.3,4 X-ray crystallography has revealed the detailed interactions of these and other inhibitors O O tBu with bromodomain acetyl-lysine sites, providing a compelling N NHEt N O MeO 30 rationale to pursue this domain class through target-based lead discovery and optimisation approaches. The breadth of published N S N bromodomain inhibitors, especially those for the BET family, has N N been comprehensively reviewed elsewhere.7,8 In this article we N 1 (I-BET762) N 2 (JQ-1) will concentrate on case histories using fragment approaches, O 35 addressing questions relevant to fragment-based drug discovery NH Cl within this target class of related proteins. These include the N N opportunities of targeting a conserved site, the advantages from HO2C transferring chemical knowledge between targets, and the N HN challenges of achieving selectivity and chemical novelty. O 4 (I-BET726) 40 Bromodomain structure, acetyl-lysine recognition N and mimicry 3 (I-BET151) O O N At least 42 human genes contain one or more bromodomains, Fig. 1 Some BET inhibitors discovered directly or indirectly through cell- modules whose function is to bind appropriately lysine-acetylated based screening. modified forms of their targets (Figure 2). Although other 45 interacting proteins have been reported, histone tails are the most commonly known binding partners. In this context, the role of This journal is © The Royal Society of Chemistry [year] [journal] , [year], [vol] , 00–00 | 1 MedChemComm Page 2 of 18 BET proteins, where two areas known as the WPF shelf (due to 20 the nearby conserved Trp-Pro-Phe motif) and the ZA channel have been found to be particular valuable in enhancing inhibitor potency and selectivity (Figure 3). For bromodomains outside the BET subfamily, these regions tend to be either more polar or relatively shallow, affording opportunities to introduce selectivity 25 for the BET proteins over other bromodomains even when starting from unselective KAc-site fragments. In this respect, the situation is reminiscent of the protein kinase family, where interactions with selectivity pockets resulting from relatively conservative amino acid substitutions can be used to tailor the 30 kinase profile of common ATP-site binding fragments. Fragment-based drug discovery Fragment-based drug discovery (FBDD) is a well-established, widely used target-based lead discovery strategy.14-17 In comparison to other approaches, FBDD screening sets contain 35 compounds of lower molecular weight. Since these are usually relatively weak binders they are tested at higher concentration. 18- 21 Among the advantages of this approach in general is the promise of efficient coverage of chemical space with smaller compound libraries, but there are other reasons why FBDD is 40 especially suitable for epigenetic histone reader modules such as bromodomains. One is the difficulty of developing viable alternatives, such as high-throughput in vitro screens, for targets Fig 2. Bromodomain phylogenetic tree, with target ligandability indicated where native binding partners and tool compounds are typically 13 by the size and colour intensity of circles (SiteMap Dscore). Targets for either of weak binding affinity or completely unknown.22 The which FBDD has been reported are marked in green. Domains lacking 45 5 either the conserved KAc-binding asparagine or water-network binding lower-throughput but sensitive direct binding methods (NMR, tyrosine are indicated by purple or green boxes respectively containing SPR etc.) commonly used in fragment screening offer a their replacement 1-letter amino acid codes. convenient solution to this challenge. Another feature of bromodomains and other histone reader modules is the ability to generate stable truncated domains for biophysical assays and 3D 50 structure determination, which are highly advantageous for fragment binding confirmation and optimisation. The availability of constructs for protein expression from public-private structural genomics groups has played a significant part in enabling this.22 Fragment-based optimisation then proceeds either by linking 55 two or more fragments that bind near to one another, or more commonly in the same way as conventional medicinal chemistry optimisation, by growing the ligand.17 Practitioners of fragment growing usually try to at least maintain high ligand efficiency (LE, defined as the binding affinity per heavy atom) during this 23 60 process. There are now several reports of fragment screens against the BET bromodomains as well as other members of the family, and a smaller but growing number of published fragment- based medicinal chemistry optimization stories. Some of these will be described below, beginning with the most active area of 65 current therapeutic interest, the BET subfamily. Fig. 3 Acetyl-lysine recognition by bromodomains, using BRD4 BD1 as 10 an example (PDB: 3uvw). The expanded area (top right) shows the conserved Asn and Tyr and the water network critical for acetyl-lysine Fragment screening against BET subfamily (cyan) binding. Below right: compound 1 (green) with BRD4 surface bromodomains showing the location of the WPF shelf and ZA channel (PDB: 4c66). The BET proteins, each containing two bromodomains (BD1 and The ZA and BC loops that flank the conserved KAc-site have the BD2), are highly tractable to a wide range of hit-finding 15 greatest sequence variation between bromodomain family 70 approaches, from cellular reporter assays to virtual members. These regions are responsible for the selective binding- screening.6,24,25 This, together with the well-validated biology of partner recognition necessary for correct cellular function. The BET bromodomain inhibitors, has made them popular systems best studied and understood selectivity regions are those of the for fragment screening experiments. 2 | Journal Name , [year], [vol] , 00–00 This journal is © The Royal Society of Chemistry [year] Page 3 of 18 MedChemComm 15 originating from BET family bromodomain screens, several of these fragments illustrate the ability of fragments to bind to the KAc-site of more than one bromodomain. The indolizine ( 5) is a micromolar-affinity BET fragment, which uses its ketone group as an acetyl-lysine mimetic, and which was also optimised 20 against the BAZ2A/B bromodomains (see the BAZ2A/B section below). The BRD2 BD1-bound crystal structure of 5 prompted the crystallographic screening of acetaminophen ( 9), which although too weak to detect in the binding assays was found to bind to the acetyl-lysine site of BRD2 BD1 in the same
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