Structure Enabled Design of BAZ2-ICR, A Chemical Probe Targeting the Bromodomains of BAZ2A and BAZ2B

被引：78

作者：

Drouin, Ludovic ^{[1
]}

McGrath, Sally ^{[1
]}

Vidler, Lewis R. ^{[1
]}

Chaikuad, Apirat ^{[2
]}

Monteiro, Octovia ^{[2
,3
]}

Tallant, Cynthia ^{[2
,3
]}

Philpott, Martin ^{[2
,3
]}

Rogers, Catherine ^{[2
,3
]}

Fedorov, Oleg ^{[2
,3
]}

Liu, Manjuan ^{[1
]}

Akhtar, Wasim ^{[1
]}

Hayes, Angela ^{[1
]}

Raynaud, Florence ^{[1
]}

Mueller, Susanne ^{[2
,3
]}

Knapp, Stefan ^{[2
,3
]}

Hoelder, Swen ^{[1
]}

机构：

[1] Inst Canc Res, Div Canc Therapeut, Canc Res UK Canc Therapeut Unit, London SM2 5NG, England

[2] Univ Oxford, Struct Genom Consortium, Oxford OX3 7DQ, England

[3] Univ Oxford, Target Discovery Inst, Oxford OX3 7FZ, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 58卷 / 05期

基金：

英国工程与自然科学研究理事会; 英国惠康基金; 加拿大创新基金会;

关键词：

SMALL-MOLECULE INHIBITORS; DISCOVERY; FAMILY; NORC; RECOGNITION; LIGANDS;

D O I：

10.1021/jm501963e

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The bromodomain containing proteins BAZ2A/B play essential roles in chromatin remodeling and regulation of noncoding RNAs. We present the structure based discovery of a potent, selective, and cell active inhibitor 13 (BAZ2-ICR) of the BAZ2A/B bromodomains through rapid optimization of a weakly potent starting point. A key feature of the presented inhibitors is an intramolecular aromatic stacking interaction that efficiently occupies the shallow bromodomain pockets. 13 represents an excellent chemical probe for functional studies of the BAZ2 bromodomains in vitro and in vivo.

引用

页码：2553 / 2559

页数：7

共 23 条

[1] Identification of a Sudden Cardiac Death Susceptibility Locus at 2q24.2 through Genome-Wide Association in European Ancestry Individuals
Arking, Dan E.
Junttila, M. Juhani
Goyette, Philippe
Huertas-Vazquez, Adriana
Eijgelsheim, Mark
Blom, Marieke T.
Newton-Cheh, Christopher
Reinier, Kyndaron
Teodorescu, Carmen
Uy-Evanado, Audrey
Carter-Monroe, Naima
Kaikkonen, Kari S.
Kortelainen, Marja-Leena
Boucher, Gabrielle
Lagace, Caroline
Moes, Anna
Zhao, XiaoQing
Kolodgie, Frank
Rivadeneira, Fernando
Hofman, Albert
Witteman, Jacqueline C. M.
Uitterlinden, Andre G.
Marsman, Roos F.
Pazoki, Raha
Bardai, Abdennasser
Koster, Rudolph W.
Dehghan, Abbas
Hwang, Shih-Jen
Bhatnagar, Pallav
Post, Wendy
Hilton, Gina
Prineas, Ronald J.
Li, Man
Koettgen, Anna
Ehret, Georg
Boerwinkle, Eric
Coresh, Josef
Kao, W. H. Linda
Psaty, Bruce M.
Tomaselli, Gordon F.
Sotoodehnia, Nona
Siscovick, David S.
Burke, Greg L.
Marban, Eduardo
Spooner, Peter M.
Cupples, L. Adrienne
Jui, Jonathan
Gunson, Karen
Kesaniemi, Y. Antero
Wilde, Arthur A. M.
[J]. PLOS GENETICS, 2011, 7 (06)
[2] Cheeseright TJ, 2011, CURR COMPUT-AID DRUG, V7, P190
[3] Targeting Low-Druggability Bromodomains: Fragment Based Screening and Inhibitor Design against the BAZ2B Bromodomain
Ferguson, Fleur M.
Fedorov, Oleg
Chaikuad, Apirat
Philpott, Martin
Muniz, Joao R. C.
Felletar, Ildiko
von Delft, Frank
Heightman, Tom
Knapp, Stefan
Abell, Chris
Ciulli, Alessio
[J]. JOURNAL OF MEDICINAL CHEMISTRY, 2013, 56 (24) : 10183 - 10187
[4] Targeting bromodomains: epigenetic readers of lysine acetylation
Filippakopoulos, Panagis
Knapp, Stefan
[J]. NATURE REVIEWS DRUG DISCOVERY, 2014, 13 (05) : 339 - 358
[5] The bromodomain interaction module
Filippakopoulos, Panagis
Knapp, Stefan
[J]. FEBS LETTERS, 2012, 586 (17) : 2692 - 2704
[6] Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family
Filippakopoulos, Panagis
Picaud, Sarah
Mangos, Maria
Keates, Tracy
Lambert, Jean-Philippe
Barsyte-Lovejoy, Dalia
Felletar, Ildiko
Volkmer, Rudolf
Mueller, Susanne
Pawson, Tony
Gingras, Anne-Claude
Arrowsmith, Cheryl H.
Knapp, Stefan
[J]. CELL, 2012, 149 (01) : 214 - 231
[7] Selective inhibition of BET bromodomains
Filippakopoulos, Panagis
Qi, Jun
Picaud, Sarah
Shen, Yao
Smith, William B.
Fedorov, Oleg
Morse, Elizabeth M.
Keates, Tracey
Hickman, Tyler T.
Felletar, Ildiko
Philpott, Martin
Munro, Shonagh
McKeown, Michael R.
Wang, Yuchuan
Christie, Amanda L.
West, Nathan
Cameron, Michael J.
Schwartz, Brian
Heightman, Tom D.
La Thangue, Nicholas
French, Christopher A.
Wiest, Olaf
Kung, Andrew L.
Knapp, Stefan
Bradner, James E.
[J]. NATURE, 2010, 468 (7327) : 1067 - 1073
[8] BAZ2A (TIP5) is involved in epigenetic alterations in prostate cancer and its overexpression predicts disease recurrence
Gu, Lei
Frommel, Sandra C.
Oakes, Christopher C.
Simon, Ronald
Grupp, Katharina
Gerig, Cristina Y.
Baer, Dominik
Robinson, Mark D.
Baer, Constance
Weiss, Melanie
Gu, Zuguang
Schapira, Matthieu
Kuner, Ruprecht
Sueltmann, Holger
Provenzano, Maurizio
Yaspo, Marie-Laure
Brors, Benedikt
Korbel, Jan
Schlomm, Thorsten
Sauter, Guido
Eils, Roland
Plass, Christoph
Santoro, Raffaella
[J]. NATURE GENETICS, 2015, 47 (01) : 22 - +
[9] Discovery and Optimization of Small-Molecule Ligands for the CBP/p300 Bromodomains
Hay, Duncan A.
Fedorov, Oleg
Martin, Sarah
Singleton, Dean C.
Tallant, Cynthia
Wells, Christopher
Picaud, Sarah
Philpott, Martin
Monteiro, Octovia P.
Rogers, Catherine M.
Conway, Stuart J.
Rooney, Timothy P. C.
Tumber, Anthony
Yapp, Clarence
Filippakopoulos, Panagis
Bunnage, Mark E.
Mueller, Susanne
Knapp, Stefan
Schofield, Christopher J.
Brennan, Paul E.
[J]. JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2014, 136 (26) : 9308 - 9319
[10] A novel family of bromodomain genes
Jones, MH
Hamana, N
Nezu, J
Shimane, M
[J]. GENOMICS, 2000, 63 (01) : 40 - 45

← 1 2 3 →