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Angew Chem Int Ed Engl. 2017 Jan 16;56(3):827-831. doi: 10.1002/anie.201610816. Epub 2016 Dec 14.

Discovery of a PCAF Bromodomain Chemical Probe.

Author information

1
Structural Genomics Consortium & Target Discovery Institute, University of Oxford, NDM Research Building, Roosevelt Drive, Oxford, OX3 7DQ and OX3 7FZ, UK.
2
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
3
Department of Chemistry, Simon Fraser University, Burnaby, V5A 1S6, Canada.
4
Dipartimento di Chimica, Università degli Studi di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185, Roma, Italy.
5
ARUK Oxford Drug Discovery Institute, University of Oxford, Oxford, OX3 7FZ, UK.
6
Johann Wolfgang Goethe-University, Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, 60438, Frankfurt am Main, Germany.
7
Promega Corporation, 2800 Woods Hollow Road, Madison, WI, 153611, USA.
8
Structural Genomics Consortium, MaRS South Tower, Suite 732, 101 College Street, Toronto, Ontario, M5G 1LZ, Canada.
9
Nuffield Department of Medicine and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, OX3 7FZ, UK.
10
UCB Pharma Ltd, Slough, SL1 3WE, UK.

Abstract

The p300/CBP-associated factor (PCAF) and related GCN5 bromodomain-containing lysine acetyl transferases are members of subfamily I of the bromodomain phylogenetic tree. Iterative cycles of rational inhibitor design and biophysical characterization led to the discovery of the triazolopthalazine-based L-45 (dubbed L-Moses) as the first potent, selective, and cell-active PCAF bromodomain (Brd) inhibitor. Synthesis from readily available (1R,2S)-(-)-norephedrine furnished L-45 in enantiopure form. L-45 was shown to disrupt PCAF-Brd histone H3.3 interaction in cells using a nanoBRET assay, and a co-crystal structure of L-45 with the homologous Brd PfGCN5 from Plasmodium falciparum rationalizes the high selectivity for PCAF and GCN5 bromodomains. Compound L-45 shows no observable cytotoxicity in peripheral blood mononuclear cells (PBMC), good cell-permeability, and metabolic stability in human and mouse liver microsomes, supporting its potential for in vivo use.

KEYWORDS:

bromodomains; chemical probes; epigenetics; medicinal chemistry; structure-based design

PMID:
27966810
PMCID:
PMC5412877
DOI:
10.1002/anie.201610816
[Indexed for MEDLINE]
Free PMC Article

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