Fragment-Based Screening of the Bromodomain of ATAD2

Harner, Mary J.; Chauder, Brian A.; Phan, Jason; Fesik, Stephen W.

doi:10.1021/jm501035j

Cited by 77 publications

(85 citation statements)

References 18 publications

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“…However, for BRPF1B, the displacement of W1 was predicted to carry a large free energy penalty of about 1 kcal mol −1 . Harner et al 9 showed instead how W4 could be displaced from ATAD2 by a fragment containing an aminothiazole group (fragment 12; PDB-ID 4TZ8). W4 was indeed predicted to be the second least stable site in ATAD2.…”

Section: General Approachmentioning

confidence: 99%

“…Recent studies have reported the complete or partial displacement of this four-water network. In 2014, Harner et al 9 reported the discovery an aniline-containing tricyclic fragment that was shown to bind deep into ATAD2, displacing all four conserved water molecules. In 2015, Fedorov et al 10 reported the displacement of all four conserved waters by salicylic acid from the binding pockets of a number of Family VIII bromodomains.…”

mentioning

confidence: 99%

“…Other studies have noticed the displacement of a single water molecule in specific bromodomains. For instance, Harner et al 9 found that an aminotetrahydrothiazole fragment could displace W4 from ATAD2. Cox et al 14 noticed the displacement of W1 from the binding pocket of PHIP(2) (in Family III) by a thiourea fragment, while Zhu and Caflisch 15 reported the displacement of W1 from BRPF1 (a member of Family IV) by an isoquinolinone fragment.…”

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confidence: 99%

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Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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Conserved water molecules are of interest in drug design, as displacement of such waters can lead to higher affinity ligands, and in some cases, contribute towards selectivity. Bromodomains, small protein domains involved in the epigenetic regulation of gene transcription, display a network of four conserved water molecules in their binding pockets and have recently been the focus of intense medicinal chemistry efforts. Understanding why certain bromodomains have displaceable water molecules and others do not is extremely challenging, and it remains unclear which water molecules in a given bromodomain can be targeted for displacement. Here we estimate the stability of the conserved water molecules in 35 bromodomains via binding free energy calculations using all-atom grand canonical Monte Carlo simulations. Encouraging quantitative agreement to the available experimental evidence is found. We thus discuss the expected ease of water displacement in different bromodomains and the implications for ligand selectivity.

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Section: General Approachmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo

et al. 2018

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“…Equally encouraging are inhibitors that have now been identified for more difficult to drug bromodomains, 18 such as BAZ2B 19, 20 and ATAD2A. 21-23 Unlike the BET sub-family, which contain two bromodomains that primarily drive their binding and therefore function, a large proportion of the other BCPs contain auxiliary domains, many with diverse and sometimes unknown functions. These multi-domain containing BCPs can also be part of multi-protein complexes.…”

Section: Introductionmentioning

confidence: 99%

Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor

et al. 2015

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The bromodomain containing proteins TRIM24 (Tripartite motif containing protein 24) and BRPF1 (bromodomain and PHD finger containing protein 1) are involved in the epigenetic regulation of gene expression and have been implicated in human cancer. Overexpression of TRIM24 correlates with poor patient prognosis and BRPF1 is a scaffolding protein required for the assembly of histone acetyltransferase complexes, where the gene of MOZ (monocytic leukemia zinc finger protein) was first identified as a recurrent fusion partner in leukemia patients (8p11 chromosomal rearrangements). Here, we present the structure guided development of a series of N,N-dimethyl benzimidazolone bromodomain inhibitors through the iterative use of X-ray cocrystal structures. A unique binding mode enabled the design of a potent and selective inhibitor, 8i (IACS-9571) with low nanomolar affinities for TRIM24 and BRPF1 (ITC Kd = 31 nM and 14 nM, respectively). With its excellent cellular potency (EC50 = 50 nM) and favorable pharmacokinetic properties (F = 29%), 8i is a high-quality chemical probe for the evaluation of TRIM24 and/or BRPF1 bromodomain function in vitro and in vivo.

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“…Since at early stages of the discovery process, FBDD is principally a hit-finding activity, it is beneficial that the protein is uniformly labeled. If protein supply is not limiting, fragment-based approaches can be applied on an unconventionally large scale, as illustrated by a study describing the discovery of smallmolecule inhibitors of the bromodomain of ATAD2 (Harner, Chauder, Phan, & Fesik, 2014). The authors screened a library of approximately 13,800 fragments (in mixtures of 12) by protein observation using uniformly 15 N-labeled bromodomain of ATAD2.…”

Section: Applications In Drug Discoverymentioning

confidence: 99%