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Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.

ABSTRACT: TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.

SUBMITTER: Bennett J

PROVIDER: S-EPMC4770308 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF.

Bennett James J Fedorov Oleg O Tallant Cynthia C Monteiro Octovia O Meier Julia J Gamble Vicky V Savitsky Pavel P Nunez-Alonso Graciela A GA Haendler Bernard B Rogers Catherine C Brennan Paul E PE Müller Susanne S Knapp Stefan S

Journal of medicinal chemistry 20150520 4

TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/TR ...[more]

PMID: 25974391

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NMR Molecular Replacement Provides New Insights into Binding Modes to Bromodomains of BRD4 and TRIM24.

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