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Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis.

Myrianthopoulos V, Gaboriaud-Kolar N, Tallant C, Hall ML, Grigoriou S, Brownlee PM, Fedorov O, Rogers C, Heidenreich D, Wanior M, Drosos N, Mexia N, Savitsky P, Bagratuni T, Kastritis E, Terpos E, Filippakopoulos P, Müller S, Skaltsounis AL, Downs JA, Knapp S, Mikros E
J Med Chem 59 8787-8803 (2016)
Related entries: 5hrv, 5hrx, 5ii1, 5ii2, 5iid

Cited: 17 times
EuropePMC logo PMID: 27617704

Abstract

Bromodomains (BRDs) are epigenetic interaction domains currently recognized as emerging drug targets for development of anticancer or anti-inflammatory agents. In this study, development of a selective ligand of the fifth BRD of polybromo protein-1 (PB1(5)) related to switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complexes is presented. A compound collection was evaluated by consensus virtual screening and a hit was identified. The biophysical study of protein-ligand interactions was performed using X-ray crystallography and isothermal titration calorimetry. Collective data supported the hypothesis that affinity improvement could be achieved by enhancing interactions of the complex with the solvent. The derived SAR along with free energy calculations and a consensus hydration analysis using WaterMap and SZmap algorithms guided rational design of a set of novel analogues. The most potent analogue demonstrated high affinity of 3.3 μM and an excellent selectivity profile, thus comprising a promising lead for the development of chemical probes targeting PB1(5).

Articles - 5hrw mentioned but not cited (1)

  1. Discovery and Optimization of a Selective Ligand for the Switch/Sucrose Nonfermenting-Related Bromodomains of Polybromo Protein-1 by the Use of Virtual Screening and Hydration Analysis. Myrianthopoulos V, Gaboriaud-Kolar N, Tallant C, Hall ML, Grigoriou S, Brownlee PM, Fedorov O, Rogers C, Heidenreich D, Wanior M, Drosos N, Mexia N, Savitsky P, Bagratuni T, Kastritis E, Terpos E, Filippakopoulos P, Müller S, Skaltsounis AL, Downs JA, Knapp S, Mikros E. J Med Chem 59 8787-8803 (2016)


Reviews citing this publication (3)

  1. Exploiting vulnerabilities of SWI/SNF chromatin remodelling complexes for cancer therapy. Wanior M, Krämer A, Knapp S, Joerger AC. Oncogene 40 3637-3654 (2021)
  2. Assays and technologies for developing proteolysis targeting chimera degraders. Liu X, Zhang X, Lv D, Yuan Y, Zheng G, Zhou D. Future Med Chem 12 1155-1179 (2020)
  3. Recent progress and structural analyses of domain-selective BET inhibitors. Divakaran A, Harki DA, Pomerantz WCK. Med Res Rev 43 972-1018 (2023)

Articles citing this publication (13)

  1. BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhöfer-Wölfer K, Wöhrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu MY, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB, Ciulli A. Nat Chem Biol 15 672-680 (2019)
  2. Structure-Based Discovery of a Selective KDM5A Inhibitor that Exhibits Anti-Cancer Activity via Inducing Cell Cycle Arrest and Senescence in Breast Cancer Cell Lines. Yang GJ, Ko CN, Zhong HJ, Leung CH, Ma DL. Cancers (Basel) 11 E92 (2019)
  3. Individual Bromodomains of Polybromo-1 Contribute to Chromatin Association and Tumor Suppression in Clear Cell Renal Carcinoma. Porter EG, Dykhuizen EC. J Biol Chem 292 2601-2610 (2017)
  4. Benzoisoquinolinediones as Potent and Selective Inhibitors of BRPF2 and TAF1/TAF1L Bromodomains. Bouché L, Christ CD, Siegel S, Fernández-Montalván AE, Holton SJ, Fedorov O, Ter Laak A, Sugawara T, Stöckigt D, Tallant C, Bennett J, Monteiro O, Díaz-Sáez L, Siejka P, Meier J, Pütter V, Weiske J, Müller S, Huber KVM, Hartung IV, Haendler B. J Med Chem 60 4002-4022 (2017)
  5. Large-scale analysis of water stability in bromodomain binding pockets with grand canonical Monte Carlo. Aldeghi M, Ross GA, Bodkin MJ, Essex JW, Knapp S, Biggin PC. Commun Chem 1 19 (2018)
  6. Euryops pectinatus L. Flower Extract Inhibits P-glycoprotein and Reverses Multi-Drug Resistance in Cancer Cells: A Mechanistic Study. M Elkady W, M Ayoub I, Abdel-Mottaleb Y, ElShafie MF, Wink M. Molecules 25 E647 (2020)
  7. Nitroalkanes as electrophiles: synthesis of triazole-fused heterocycles with neuroblastoma differentiation activity. Aksenov NA, Aksenov AV, Kirilov NK, Arutiunov NA, Aksenov DA, Maslivetc V, Zhao Z, Du L, Rubin M, Kornienko A. Org Biomol Chem 18 6651-6664 (2020)
  8. Selective and Cell-Active PBRM1 Bromodomain Inhibitors Discovered through NMR Fragment Screening. Shishodia S, Nuñez R, Strohmier BP, Bursch KL, Goetz CJ, Olp MD, Jensen DR, Fenske TG, Ordonez-Rubiano SC, Blau ME, Roach MK, Peterson FC, Volkman BF, Dykhuizen EC, Smith BC. J Med Chem 65 13714-13735 (2022)
  9. Combined Virtual and Experimental Screening for CK1 Inhibitors Identifies a Modulator of p53 and Reveals Important Aspects of in Silico Screening Performance. Myrianthopoulos V, Lozach O, Zareifi D, Alexopoulos L, Meijer L, Gorgoulis VG, Mikros E. Int J Mol Sci 18 E2102 (2017)
  10. Design and Synthesis of LM146, a Potent Inhibitor of PB1 with an Improved Selectivity Profile over SMARCA2. Mélin L, Gesner E, Attwell S, Kharenko OA, van der Horst EH, Hansen HC, Gagnon A. ACS Omega 6 21327-21338 (2021)
  11. A facile consensus ranking approach enhances virtual screening robustness and identifies a cell-active DYRK1α inhibitor. Mavrogeni ME, Pronios F, Zareifi D, Vasilakaki S, Lozach O, Alexopoulos L, Meijer L, Myrianthopoulos V, Mikros E. Future Med Chem 10 2411-2430 (2018)
  12. Exploring ensembles of bioactive or virtual analogs of X-ray ligands for shape similarity searching. Miyao T, Bajorath J. J Comput Aided Mol Des 32 759-767 (2018)
  13. Rational Design and Development of Selective BRD7 Bromodomain Inhibitors and Their Activity in Prostate Cancer. Ordonez-Rubiano SC, Maschinot CA, Wang S, Sood S, Baracaldo-Lancheros LF, Strohmier BP, McQuade AJ, Smith BC, Dykhuizen EC. J Med Chem 66 11250-11270 (2023)


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