3,5-Dimethylisoxazoles Act As Acetyl-lysine-mimetic Bromodomain Ligands

被引：183

作者：

Hewings, David S. ^{[1
,2
]}

Wang, Minghua ^{[2
]}

Philpott, Martin ^{[2
]}

Fedorov, Oleg ^{[2
]}

Uttarkar, Sagar ^{[2
]}

Filippakopoulos, Panagis ^{[2
]}

Picaud, Sarah ^{[2
]}

Vuppusetty, Chaitanya ^{[2
]}

Marsden, Brian ^{[2
]}

Knapp, Stefan ^{[2
]}

Conway, Stuart J. ^{[1
]}

Heightman, Tom D. ^{[2
]}

机构：

[1] Univ Oxford, Dept Chem, Chem Res Lab, Oxford OX1 3TA, England

[2] Univ Oxford, Struct Genom Consortium, Nuffield Dept Clin Med, Oxford OX3 7DQ, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 19期

基金：

英国惠康基金;

关键词：

CGRP RECEPTOR ANTAGONISTS; HISTONE ACETYLATION; STRUCTURAL BASIS; PROTEIN; INTERACTS; FAMILY;

D O I：

10.1021/jm200640v

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Histone-lysine acetylation is a vital chromatin post-translational modification involved in the epigenetic regulation of gene transcription. Bromodomains bind acetylated lysines, acting as readers of the histone-acetylation code. Competitive inhibitors of this interaction have antiproliferative and anti-inflammatory properties. With 57 distinct bromodomains known, the discovery of subtype-selective inhibitors of the histone bromodomain interaction is of great importance. We have identified the 3,5-dimethylisoxazole moiety as a novel acetyl-lysine bioisostere, which displaces acetylated histone-mimicking peptides from bromodomains. Using X-ray crystallographic analysis, we have determined the interactions responsible for the activity and selectivity of 4-substituted 3,5-dimethylisoxazoles against a selection of phylogenetically diverse bromodomains. By exploiting these interactions, we have developed compound 4d, which has IC50 values of < 5 mu M for the bromodomain-containing proteins BRD2(1) and BRD4(1). These compounds are promising leads for the further development of selective probes for the bromodomain and extra C-terminal domain (BET) family and CREBBP bromodomains.

引用

页码：6761 / 6770

页数：10

共 41 条

[1] ICM - A NEW METHOD FOR PROTEIN MODELING AND DESIGN - APPLICATIONS TO DOCKING AND STRUCTURE PREDICTION FROM THE DISTORTED NATIVE CONFORMATION [J].

ABAGYAN, R ;

TOTROV, M ;

KUZNETSOV, D .

JOURNAL OF COMPUTATIONAL CHEMISTRY, 1994, 15 (05) :488-506

[2] Deciphering the transcriptional histone acetylation code for a human gene [J].

Agalioti, T ;

Chen, GY ;

Thanos, D .

CELL, 2002, 111 (03) :381-392

[3] A Small Molecule Binding to the Coactivator CREB-Binding Protein Blocks Apoptosis in Cardiomyocytes [J].

Borah, Jagat C. ;

Mujtaba, Shiraz ;

Karakikes, Ioannis ;

Zeng, Lei ;

Muller, Michaela ;

Patel, Jigneshkumar ;

Moshkina, Natasha ;

Morohashi, Keita ;

Zhang, Weijia ;

Gerona-Navarro, Guillermo ;

Hajjar, Roger J. ;

Zhou, Ming-Ming .

CHEMISTRY & BIOLOGY, 2011, 18 (04) :531-541

[4] Virtual Ligand Screening of the p300/CBP Histone Acetyltransferase: Identification of a Selective Small Molecule Inhibitor [J].

Bowers, Erin M. ;

Yan, Gai ;

Mukherjee, Chandrani ;

Orry, Andrew ;

Wang, Ling ;

Holbert, Marc A. ;

Crump, Nicholas T. ;

Hazzalin, Catherine A. ;

Liszczak, Glen ;

Yuan, Hua ;

Larocca, Cecilia ;

Saldanha, S. Adrian ;

Abagyan, Ruben ;

Sun, Yan ;

Meyers, David J. ;

Marmorstein, Ronen ;

Mahadevan, Louis C. ;

Alani, Rhoda M. ;

Cole, Philip A. .

CHEMISTRY & BIOLOGY, 2010, 17 (05) :471-482

[5] Structural basis of inhibitor specificity of the human protooncogene proviral insertion site in Moloney murine leukemia virus (PIM-1) kinase [J].

Bullock, AN ;

Debreczeni, JÉ ;

Fedorov, OY ;

Nelson, A ;

Marsden, BD ;

Knapp, S .

JOURNAL OF MEDICINAL CHEMISTRY, 2005, 48 (24) :7604-7614

[6] Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: Optimization of the 4-substituted piperidine [J].

Burgey, Christopher S. ;

Stump, Craig A. ;

Nguyen, Diem N. ;

Deng, James Z. ;

Quigley, Amy G. ;

Norton, Beth R. ;

Bell, Ian M. ;

Mosser, Scott D. ;

Salvatore, Christopher A. ;

Rutledge, Ruth Z. ;

Kane, Stefanie A. ;

Koblan, Kenneth S. ;

Vacca, Joseph P. ;

Graham, Samuel L. ;

Williams, Theresa M. .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2006, 16 (19) :5052-5056

[7] Lysine Acetylation Targets Protein Complexes and Co-Regulates Major Cellular Functions [J].

Choudhary, Chunaram ;

Kumar, Chanchal ;

Gnad, Florian ;

Nielsen, Michael L. ;

Rehman, Michael ;

Walther, Tobias C. ;

Olsen, Jesper V. ;

Mann, Matthias .

SCIENCE, 2009, 325 (5942) :834-840

[8] Discovery and Characterizatlion of Small Molecule Inhibitors of the BET Family Bromodomains [J].

Chung, Chun-wa ;

Coste, Herve ;

White, Julia H. ;

Mirguet, Olivier ;

Wilde, Jonathan ;

Gosmini, Romain L. ;

Delves, Chris ;

Magny, Sylvie M. ;

Woodward, Robert ;

Hughes, Stephen A. ;

Boursier, Eric V. ;

Flynn, Helen ;

Bouillot, Anne M. ;

Bamborough, Paul ;

Brusq, Jean-Marie G. ;

Gellibert, Francoise J. ;

Jones, Emma J. ;

Riou, Alizon M. ;

Homes, Paul ;

Martin, Sandrine L. ;

Uings, Iain J. ;

Toum, Jerome ;

Clement, Catherine A. ;

Boullay, Anne-Benedicte ;

Grimley, Rachel L. ;

Blande, Florence M. ;

Prinjha, Rab K. ;

Lee, Kevin ;

Kirilovsky, Jorge ;

Nicodeme, Edwige .

JOURNAL OF MEDICINAL CHEMISTRY, 2011, 54 (11) :3827-3838

[9] Bromodomain 4 activation predicts breast cancer survival [J].

Crawford, Nigel P. S. ;

Alsarraj, Jude ;

Lukes, Luanne ;

Walker, Renard C. ;

Officewala, Jennifer S. ;

Yang, Howard H. ;

Lee, Maxwell P. ;

Ozato, Keiko ;

Hunter, Kent W. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (17) :6380-6385

[10] Structure and ligand of a histone acetyltransferase bromodomain [J].

Dhalluin, C ;

Carlson, JE ;

Zeng, L ;

He, C ;

Aggarwal, AK ;

Zhou, MM .

NATURE, 1999, 399 (6735) :491-496

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