Development of Selective CBP/P300 Benzoxazepine Bromodomain Inhibitors.
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.
Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München , Butenandtstrasse 5-13, D-81377 München, Germany.
Tobias A
TA
Popp
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI) , Roosevelt Drive, Oxford OX3 7BN, U.K.
Cynthia
C
Tallant
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI) , Roosevelt Drive, Oxford OX3 7BN, U.K.
Catherine
C
Rogers
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI) , Roosevelt Drive, Oxford OX3 7BN, U.K.
Oleg
O
Fedorov
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI) , Roosevelt Drive, Oxford OX3 7BN, U.K.
Paul E
PE
Brennan
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Nuffield Department of Clinical Medicine, University of Oxford, Target Discovery Institute (TDI) , Roosevelt Drive, Oxford OX3 7BN, U.K.
Susanne
S
Müller
Nuffield Department of Clinical Medicine, University of Oxford, Structural Genomics Consortium , Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, U.K.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Johann Wolfgang Goethe-University , Max-von-Laue-Strasse 9, D-60438 Frankfurt am Main, Germany.
Stefan
S
Knapp
Department für Pharmazie-Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität München , Butenandtstrasse 5-13, D-81377 München, Germany.
Franz
F
Bracher
D048588:Benzoxazines / Q000737:chemistry* / Q000494:pharmacology*; D055808:Drug Discovery; D006801:Humans; D008958:Models, Molecular; D000072417:Protein Domains / Q000187:drug effects; D060066:Protein Interaction Maps / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D048588:Benzoxazines; D050880:p300-CBP Transcription Factors