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Development of selective CBP/P300 benzoxazepine bromodomain inhibitors

DOI: 10.1021/acs.jmedchem.6b00774 DOI Help

Authors: Tobias A. Popp (Ludwig-Maximilians-Universität München) , Cynthia Tallant (Structural Genomics Consortium, University of Oxford) , Catherine Rogers (Structural Genomics Consortium, University of Oxford) , Oleg Fedorov (Structural Genomics Consortium, University of Oxford) , Paul E. Brennan (Structural Genomics Consortium, University of Oxford) , Susanne Müller (Structural Genomics Consortium, University of Oxford) , Stefan Knapp (Structural Genomics Consortium, University of Oxford) , Franz Bracher (Ludwig-Maximilians-Universität München)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 59 , PAGES 8889 - 8912

State: Published (Approved)
Published: October 2016

Abstract: CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein–protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.

Journal Keywords: Reagents; Amides; Scaffolds; Inhibitors; Selectivity

Subject Areas: Biology and Bio-materials, Chemistry, Medicine


Instruments: I04-Macromolecular Crystallography

Added On: 06/12/2016 16:17

Discipline Tags:

Health & Wellbeing Biochemistry Chemistry Structural biology Organic Chemistry Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)