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Bivalent BET Bromodomain Inhibitors Confer Increased Potency and Selectivity for BRDT via Protein Conformational Plasticity.

Guan X, Cheryala N, Karim RM, Chan A, Berndt N, Qi J, Georg GI, Schönbrunn E
J Med Chem (2022)
Related entries: 7l9m, 7la9, 7mr5, 7mr6, 7mr7, 7mr9, 7mra, 7mrb, 7mrd, 7mrg, 7mrh, 8cza

Cited: 5 times
EuropePMC logo PMID: 35867655

Abstract

Bromodomain and extraterminal domain (BET) proteins are important regulators of gene transcription and chromatin remodeling. BET family members BRD4 and BRDT are validated targets for cancer and male contraceptive drug development, respectively. Due to the high structural similarity of the acetyl-lysine binding sites, most reported inhibitors lack intra-BET selectivity. We surmised that protein-protein interactions induced by bivalent inhibitors may differ between BRD4 and BRDT, conferring an altered selectivity profile. Starting from nonselective monovalent inhibitors, we developed cell-active bivalent BET inhibitors with increased activity and selectivity for BRDT. X-ray crystallographic and solution studies revealed unique structural states of BRDT and BRD4 upon interaction with bivalent inhibitors. Varying spacer lengths and symmetric vs unsymmetric connections resulted in the same dimeric states, whereas different chemotypes induced different dimers. The findings indicate that the increased intra-BET selectivity of bivalent inhibitors is due to the differential plasticity of BET bromodomains upon inhibitor-induced dimerization.

Reviews citing this publication (3)

  1. BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications. To KKW, Xing E, Larue RC, Li PK. Molecules 28 3043 (2023)
  2. Male contraception: narrative review of ongoing research. Louwagie EJ, Quinn GFL, Pond KL, Hansen KA. Basic Clin Androl 33 30 (2023)
  3. 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)

Articles citing this publication (2)

  1. Design and Characterization of 1,3-Dihydro-2H-benzo[d]azepin-2-ones as Rule-of-5 Compliant Bivalent BET Inhibitors. Bamborough P, Chung CW, Goodwin NC, Mitchell DJ, Neipp CE, Phillipou A, Preston A, Prinjha RK, Soden PE, Watson RJ, Demont EH. ACS Med Chem Lett 14 1231-1236 (2023)
  2. Small Molecule Ligands of the BET-like Bromodomain, SmBRD3, Affect Schistosoma mansoni Survival, Oviposition, and Development. Schiedel M, McArdle DJB, Padalino G, Chan AKN, Forde-Thomas J, McDonough M, Whiteland H, Beckmann M, Cookson R, Hoffmann KF, Conway SJ. J Med Chem 66 15801-15822 (2023)


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