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Identification of a chemical probe for bromo and extra C-terminal bromodomain inhibition through optimization of a fragment-derived hit.

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Fish PV, Filippakopoulos P, Bish G, Brennan PE, Bunnage ME, Cook AS, Federov O, Gerstenberger BS, Jones H, Knapp S, Marsden B, Nocka K, Owen DR, Philpott M, Picaud S, Primiano MJ, Ralph MJ, Sciammetta N, Trzupek JD
OpenAccess logo J Med Chem 55 9831-7 (2012)
Related entries: 4e96, 4hbv, 4hbw, 4hbx

Cited: 97 times
EuropePMC logo PMID: 23095041

Abstract

The posttranslational modification of chromatin through acetylation at selected histone lysine residues is governed by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The significance of this subset of the epigenetic code is interrogated and interpreted by an acetyllysine-specific protein-protein interaction with bromodomain reader modules. Selective inhibition of the bromo and extra C-terminal domain (BET) family of bromodomains with a small molecule is feasible, and this may represent an opportunity for disease intervention through the recently disclosed antiproliferative and anti-inflammatory properties of such inhibitors. Herein, we describe the discovery and structure-activity relationship (SAR) of a novel, small-molecule chemical probe for BET family inhibition that was identified through the application of structure-based fragment assessment and optimization techniques. This has yielded a potent, selective compound with cell-based activity (PFI-1) that may further add to the understanding of BET family function within the bromodomains.

Reviews citing this publication (27)

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  23. Chemogenomics for drug discovery: clinical molecules from open access chemical probes. Quinlan RBA, Brennan PE. RSC Chem Biol 2 759-795 (2021)
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  25. Bromodomain and BET family proteins as epigenetic targets in cancer therapy: their degradation, present drugs, and possible PROTACs. Muddassir M, Soni K, Sangani CB, Alarifi A, Afzal M, Abduh NAY, Duan Y, Bhadja P. RSC Adv 11 612-636 (2020)
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Articles citing this publication (70)



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