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

Lucas, Simon; Atkinson, Sophie; Bamborough, Paul; Barnett, Heather; Chung, Chun‐wa; Gordon, Laurie J.; Mitchell, Darren J.; Phillipou, Alexander; Prinjha, Rab K.; Sheppard, Robert J.; Tomkinson, Nicholas C. O.; Watson, Robert J.; Demont, Emmanuel H.

doi:10.1021/acs.jmedchem.0c00021

Cited by 19 publications

(19 citation statements)

References 60 publications

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“…Halogen-bonding interactions between small molecules and bromodomains have only been reported recently. These interactions have been found with a different site in the histone binding pocket . In addition, the dimethylethylamino group formed a water-bridging hydrogen-bonding interaction with Asp144 via a structured water molecule.…”

Section: Resultsmentioning

confidence: 96%

“…With this information, an N,N-dimethylethylamino group was installed on inhibitors 1 and 23 to yield two new inhibitors 25, now referred to as DW34, and 26. By the FA assay, these inhibitors were more potent with IC 50 values of 0.137 ± 0.02 μM (DW34) and 0.110 ± 0.02 μM (26), respectively (Figure 4A). This represents a potency increase of >10-fold and makes inhibitors DW34 and 26 similar in potency to (+)-JQ1 in the same FA assay.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…These interactions have been found with a different site in the histone binding pocket. 26 In addition, the dimethylethylamino group formed a water-bridging hydrogen-bonding interaction with Asp144 via a structured water molecule. Although halogenbonding interactions were not possible for DW34, a cocrystal structure also showed a water bridging hydrogen-bonding interaction with Asp144 via the structured water molecule (Figure 3C).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity

et al. 2021

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The bromodomain and extra terminal (BET) protein family recognizes acetylated lysines within histones and transcription factors using two N-terminal bromodomains, D1 and D2. The protein−protein interactions between BET bromodomains, acetylated histones, and transcription factors are therapeutic targets for BET-related diseases, including inflammatory disease and cancer. Prior work demonstrated that methylated-1,2,3triazoles are suitable N-acetyl lysine mimetics for BET inhibition. Here we describe a structure−activity relationship study of triazole-based inhibitors that improve affinity, D1 selectivity, and microsomal stability. These outcomes were accomplished by targeting a nonconserved residue, Asp144 and a conserved residue, Met149, on BRD4 D1. The lead inhibitors DW34 and 26 have a BRD4 D1 K d of 12 and 6.4 nM, respectively. Cellular activity was demonstrated through suppression of c-Myc expression in MM.1S cells and downregulation of IL-8 in TNF-α-stimulated A549 cells. These data indicate that DW34 and 26 are new leads to investigate the anticancer and anti-inflammatory activity of BET proteins.

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Section: Resultsmentioning

confidence: 96%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity

et al. 2021

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“…Optimization of compound 25 led to compound 26, which showed sub-micromolar ATAD2 inhibition and at least 10-fold selectivity over the BET bromodomains, such as CECR2, TAF1 and BRPF3. Using compound 26 as the starting point, further optimization toward ATAD2 and CECR2 (cat eye syndrome chromosome region, candidate 2) gave GSK232 (27), which showed high selectivity, cellular penetration, and excellent physicochemical properties [135]. The phenyl sulfonamides exhibited a novel mode of binding to non-bromodomain and non-BET bromodomains through displacement of a normally conserved network of four water molecules (Figure 10).…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

Zhang

Cheng

et al. 2021

European Journal of Medicinal Chemistry

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…Further optimization of this series against the bromodomain of ATAD2 and also against CECR2, including screening against a broader bromodomain panel, is described in a second publication. 36 The remainder of this manuscript focuses on understanding the interactions of the core phenylsulfonamide moiety with ATAD2.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

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

et al. 2019

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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 lesstractable targets.

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

Cited by 19 publications

References 60 publications

4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity

4-Methyl-1,2,3-Triazoles as N-Acetyl-Lysine Mimics Afford Potent BET Bromodomain Inhibitors with Improved Selectivity

AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors

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

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