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

Demont EH, Chung CW, Furze RC, Grandi P, Michon AM, Wellaway C, Barrett N, Bridges AM, Craggs PD, Diallo H, Dixon DP, Douault C, Emmons AJ, Jones EJ, Karamshi BV, Locke K, Mitchell DJ, Mouzon BH, Prinjha RK, Roberts AD, Sheppard RJ, Watson RJ, Bamborough P
J Med Chem 58 5649-73 (2015)
Related entries: 5a5n, 5a5o, 5a5p, 5a5q, 5a5s

Cited: 38 times
EuropePMC logo PMID: 26155854

Abstract

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.

Reviews - 5a5r mentioned but not cited (3)

  1. AAA ATPases as therapeutic targets: Structure, functions, and small-molecule inhibitors. Zhang G, Li S, Cheng KW, Chou TF. Eur J Med Chem 219 113446 (2021)
  2. Process of Fragment-Based Lead Discovery-A Perspective from NMR. Ma R, Wang P, Wu J, Ruan K. Molecules 21 E854 (2016)
  3. ATPase family AAA domain-containing protein 2 (ATAD2): From an epigenetic modulator to cancer therapeutic target. Fu J, Zhang J, Chen X, Liu Z, Yang X, He Z, Hao Y, Liu B, Yao D. Theranostics 13 787-809 (2023)


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  1. Bromodomain inhibitors and cancer therapy: From structures to applications. Pérez-Salvia M, Esteller M. Epigenetics 12 323-339 (2017)
  2. Bromodomain biology and drug discovery. Zaware N, Zhou MM. Nat Struct Mol Biol 26 870-879 (2019)
  3. Metabolic circuits in neural stem cells. Kim DY, Rhee I, Paik J. Cell Mol Life Sci 71 4221-4241 (2014)
  4. Targeting epigenetic regulators for cancer therapy: modulation of bromodomain proteins, methyltransferases, demethylases, and microRNAs. Gelato KA, Adler D, Ocker M, Haendler B. Expert Opin Ther Targets 20 783-799 (2016)
  5. Selectivity on-target of bromodomain chemical probes by structure-guided medicinal chemistry and chemical biology. Galdeano C, Ciulli A. Future Med Chem 8 1655-1680 (2016)
  6. ATAD2 in cancer: a pharmacologically challenging but tractable target. Hussain M, Zhou Y, Song Y, Hameed HMA, Jiang H, Tu Y, Zhang J. Expert Opin Ther Targets 22 85-96 (2018)
  7. Chemical probes and inhibitors of bromodomains outside the BET family. Moustakim M, Clark PGK, Hay DA, Dixon DJ, Brennan PE. Medchemcomm 7 2246-2264 (2016)
  8. Progress in the Development of non-BET Bromodomain Chemical Probes. Theodoulou NH, Tomkinson NC, Prinjha RK, Humphreys PG. ChemMedChem 11 477-487 (2016)
  9. Functional Roles of Bromodomain Proteins in Cancer. Boyson SP, Gao C, Quinn K, Boyd J, Paculova H, Frietze S, Glass KC. Cancers (Basel) 13 3606 (2021)
  10. Structural features and inhibitors of bromodomains. Meslamani J, Smith SG, Sanchez R, Zhou MM. Drug Discov Today Technol 19 3-15 (2016)
  11. Tumor-Promoting ATAD2 and Its Preclinical Challenges. Liu H, Wen Q, Yan S, Zeng W, Zou Y, Liu Q, Zhang G, Zou J, Zou X. Biomolecules 12 1040 (2022)
  12. Targeting bromodomain-containing proteins: research advances of drug discovery. Pan Z, Zhao Y, Wang X, Xie X, Liu M, Zhang K, Wang L, Bai D, Foster LJ, Shu R, He G. Mol Biomed 4 13 (2023)
  13. Screening Ultra-Large Encoded Compound Libraries Leads to Novel Protein-Ligand Interactions and High Selectivity. Collie GW, Clark MA, Keefe AD, Madin A, Read JA, Rivers EL, Zhang Y. J Med Chem 67 864-884 (2024)

Articles citing this publication (22)



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