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Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain.

Ferguson FM, Fedorov O, Chaikuad A, Philpott M, Muniz JR, Felletar I, von Delft F, Heightman T, Knapp S, Abell C, Ciulli A
J Med Chem 56 10183-7 (2013)
Related entries: 4nr9, 4nrb, 4nrc

Cited: 42 times
EuropePMC logo PMID: 24304323

Abstract

Bromodomains are epigenetic reader domains that have recently become popular targets. In contrast to BET bromodomains, which have proven druggable, bromodomains from other regions of the phylogenetic tree have shallower pockets. We describe successful targeting of the challenging BAZ2B bromodomain using biophysical fragment screening and structure-based optimization of high ligand-efficiency fragments into a novel series of low-micromolar inhibitors. Our results provide attractive leads for development of BAZ2B chemical probes and indicate the whole family may be tractable.

Reviews - 4nra mentioned but not cited (1)

  1. 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)

Articles - 4nra mentioned but not cited (2)

  1. Targeting low-druggability bromodomains: fragment based screening and inhibitor design against the BAZ2B bromodomain. Ferguson FM, Fedorov O, Chaikuad A, Philpott M, Muniz JR, Felletar I, von Delft F, Heightman T, Knapp S, Abell C, Ciulli A. J Med Chem 56 10183-10187 (2013)
  2. Exploring Thiazolopyridine AV25R: Unraveling of Biological Activities, Selective Anti-Cancer Properties and In Silico Target and Binding Prediction in Hematological Neoplasms. Ladwig A, Gupta S, Ehlers P, Sekora A, Alammar M, Koczan D, Wolkenhauer O, Junghanss C, Langer P, Murua Escobar H. Molecules 28 8120 (2023)


Reviews citing this publication (12)

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Articles citing this publication (27)

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  2. Discovery of I-BRD9, a Selective Cell Active Chemical Probe for Bromodomain Containing Protein 9 Inhibition. Theodoulou NH, Bamborough P, Bannister AJ, Becher I, Bit RA, Che KH, Chung CW, Dittmann A, Drewes G, Drewry DH, Gordon L, Grandi P, Leveridge M, Lindon M, Michon AM, Molnar J, Robson SC, Tomkinson NC, Kouzarides T, Prinjha RK, Humphreys PG. J Med Chem 59 1425-1439 (2016)
  3. Structure-Guided Design of IACS-9571, a Selective High-Affinity Dual TRIM24-BRPF1 Bromodomain Inhibitor. Palmer WS, Poncet-Montange G, Liu G, Petrocchi A, Reyna N, Subramanian G, Theroff J, Yau A, Kost-Alimova M, Bardenhagen JP, Leo E, Shepard HE, Tieu TN, Shi X, Zhan Y, Zhao S, Barton MC, Draetta G, Toniatti C, Jones P, Geck Do M, Andersen JN. J Med Chem 59 1440-1454 (2016)
  4. The Bromodomain: A New Target in Emerging Epigenetic Medicine. Smith SG, Zhou MM. ACS Chem Biol 11 598-608 (2016)
  5. A poised fragment library enables rapid synthetic expansion yielding the first reported inhibitors of PHIP(2), an atypical bromodomain. Cox OB, Krojer T, Collins P, Monteiro O, Talon R, Bradley A, Fedorov O, Amin J, Marsden BD, Spencer J, von Delft F, Brennan PE. Chem Sci 7 2322-2330 (2016)
  6. Discovery and Characterization of GSK2801, a Selective Chemical Probe for the Bromodomains BAZ2A and BAZ2B. Chen P, Chaikuad A, Bamborough P, Bantscheff M, Bountra C, Chung CW, Fedorov O, Grandi P, Jung D, Lesniak R, Lindon M, Müller S, Philpott M, Prinjha R, Rogers C, Selenski C, Tallant C, Werner T, Willson TM, Knapp S, Drewry DH. J Med Chem 59 1410-1424 (2016)
  7. Molecular basis of histone tail recognition by human TIP5 PHD finger and bromodomain of the chromatin remodeling complex NoRC. Tallant C, Valentini E, Fedorov O, Overvoorde L, Ferguson FM, Filippakopoulos P, Svergun DI, Knapp S, Ciulli A. Structure 23 80-92 (2015)
  8. Structure enabled design of BAZ2-ICR, a chemical probe targeting the bromodomains of BAZ2A and BAZ2B. Drouin L, McGrath S, Vidler LR, Chaikuad A, Monteiro O, Tallant C, Philpott M, Rogers C, Fedorov O, Liu M, Akhtar W, Hayes A, Raynaud F, Müller S, Knapp S, Hoelder S. J Med Chem 58 2553-2559 (2015)
  9. Fragment-based screening of the bromodomain of ATAD2. Harner MJ, Chauder BA, Phan J, Fesik SW. J Med Chem 57 9687-9692 (2014)
  10. 9H-purine scaffold reveals induced-fit pocket plasticity of the BRD9 bromodomain. Picaud S, Strocchia M, Terracciano S, Lauro G, Mendez J, Daniels DL, Riccio R, Bifulco G, Bruno I, Filippakopoulos P. J Med Chem 58 2718-2736 (2015)
  11. Mapping the Ligand Binding Landscape. Dickson A. Biophys J 115 1707-1719 (2018)
  12. Binding hotspots of BAZ2B bromodomain: Histone interaction revealed by solution NMR driven docking. Ferguson FM, Dias DM, Rodrigues JP, Wienk H, Boelens R, Bonvin AM, Abell C, Ciulli A. Biochemistry 53 6706-6716 (2014)
  13. Cation-π interactions in CREBBP bromodomain inhibition: an electrostatic model for small-molecule binding affinity and selectivity. Cortopassi WA, Kumar K, Paton RS. Org Biomol Chem 14 10926-10938 (2016)
  14. Targeting Ligandable Pockets on Plant Homeodomain (PHD) Zinc Finger Domains by a Fragment-Based Approach. Amato A, Lucas X, Bortoluzzi A, Wright D, Ciulli A. ACS Chem Biol 13 915-921 (2018)
  15. Virtual screening in small molecule discovery for epigenetic targets. Li GB, Yang LL, Yuan Y, Zou J, Cao Y, Yang SY, Xiang R, Xiang M. Methods 71 158-166 (2015)
  16. Structure-Based Identification of Inhibitory Fragments Targeting the p300/CBP-Associated Factor Bromodomain. Chaikuad A, Lang S, Brennan PE, Temperini C, Fedorov O, Hollander J, Nachane R, Abell C, Müller S, Siegal G, Knapp S. J Med Chem 59 1648-1653 (2016)
  17. Discovery of BAZ2A bromodomain ligands. Spiliotopoulos D, Wamhoff EC, Lolli G, Rademacher C, Caflisch A. Eur J Med Chem 139 564-572 (2017)
  18. Investigation of the mycobacterial enzyme HsaD as a potential novel target for anti-tubercular agents using a fragment-based drug design approach. Ryan A, Polycarpou E, Lack NA, Evangelopoulos D, Sieg C, Halman A, Bhakta S, Eleftheriadou O, McHugh TD, Keany S, Lowe ED, Ballet R, Abuhammad A, Jacobs WR, Ciulli A, Sim E. Br J Pharmacol 174 2209-2224 (2017)
  19. Discovery of small molecules targeting the tandem tudor domain of the epigenetic factor UHRF1 using fragment-based ligand discovery. Chang L, Campbell J, Raji IO, Guduru SKR, Kandel P, Nguyen M, Liu S, Tran K, Venugopal NK, Taylor BC, Holt MV, Young NL, Samuel ELG, Jain P, Santini C, Sankaran B, MacKenzie KR, Young DW. Sci Rep 11 1121 (2021)
  20. Discovery of New Bromodomain Scaffolds by Biosensor Fragment Screening. Navratilova I, Aristotelous T, Picaud S, Chaikuad A, Knapp S, Filappakopoulos P, Hopkins AL. ACS Med Chem Lett 7 1213-1218 (2016)
  21. Structural Analysis of Small-Molecule Binding to the BAZ2A and BAZ2B Bromodomains. Dalle Vedove A, Spiliotopoulos D, D'Agostino VG, Marchand JR, Unzue A, Nevado C, Lolli G, Caflisch A. ChemMedChem 13 1479-1487 (2018)
  22. On the Importance of C-H/π and C-H⋅⋅⋅H-C Interactions in the Solid State Structure of 15-Lipoxygenase Inhibitors Based on Eugenol Derivatives. Mirzaei M, Nikpour M, Bauzá A, Frontera A. Chemphyschem 16 2260-2266 (2015)
  23. Repeat to gene expression ratios in leukemic blast cells can stratify risk prediction in acute myeloid leukemia. Onishi-Seebacher M, Erikson G, Sawitzki Z, Ryan D, Greve G, Lübbert M, Jenuwein T. BMC Med Genomics 14 166 (2021)
  24. Binding Selectivity of Inhibitors toward Bromodomains BAZ2A and BAZ2B Uncovered by Multiple Short Molecular Dynamics Simulations and MM-GBSA Calculations. Wang L, Wang Y, Yang Z, Xu S, Li H. ACS Omega 6 12036-12049 (2021)
  25. Toward more potent imidazopyridine inhibitors of Candida albicans Bdf1: Modeling the role of structural waters in selective ligand binding. Zhou Y, Overhulse JM, Dupper NJ, Guo Y, Kashemirov BA, Wei K, Govin J, Petosa C, McKenna CE. J Comput Chem 43 2121-2130 (2022)
  26. Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex. Breindl M, Spitzer D, Gerasimaitė R, Kairys V, Schubert T, Henfling R, Schwartz U, Lukinavičius G, Manelytė L. Nucleic Acids Res 52 337-354 (2024)
  27. Crystal structure of a three-tetrad, parallel, K+-stabilized human telomeric G-quadruplex at 1.35 Å resolution. Chen EV, Nicoludis JM, Powell BM, Li KS, Yatsunyk LA. Acta Crystallogr F Struct Biol Commun 79 144-150 (2023)


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