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23 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Histone recognition and large-scale structural analysis of the human bromodomain family Panagis Filippakopoulos , Sarah Picaud , Maria Mangos , Tracy Keates , Jean-Philippe Lambert , Dalia Barsyte-Lovejoy , Ildiko Felletar , Rudolf Volkmer , Susanne Müller , Tony Pawson , Anne-Claude Gingras , Cheryl h. Arrowsmith , Stefan Knapp Cell 149 (1), 214 - 231 DOI: 10.1016/j.cell.2012.02.013 PMID: 22464331 Open Access Show Abstract ▼ Abstract: Bromodomains (BRDs) are protein interaction modules that specifically recognize ?-N-lysine acetylation motifs, a key event in the reading process of epigenetic marks. The 61 BRDs in the human genome cluster into eight families based on structure/sequence similarity. Here, we present 29 high-resolution crystal structures, covering all BRD families. Comprehensive crossfamily structural analysis identifies conserved and family-specific structural features that are necessary for specific acetylation-dependent substrate recognition. Screening of more than 30 representative BRDs against systematic histone-peptide arrays identifies new BRD substrates and reveals a strong influence of flanking posttranslational modifications, such as acetylation and phosphorylation, suggesting that BRDs recognize combinations of marks rather than singly acetylated sequences. We further uncovered a structural mechanism for the simultaneous binding and recognition of diverse diacetyl-containing peptides by BRD4. These data provide a foundation for structure-based drug design of specific inhibitors for this emerging target family.	Mar 2012
I04-1-Macromolecular Crystallography (fixed wavelength)	Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family Panagis Filippakopoulos , Sarah Picaud , Oleg Fedorov , Marco Keller , Matthias Wrobel , Olaf Morgenstern , Franz Bracher , Stefan Knapp Bioorganic & Medicinal Chemistry 20 (6), 1878 - 1886 DOI: 10.1016/j.bmc.2011.10.080 PMID: 22137933 Open Access Show Abstract ▼ Abstract: Benzodiazepines are psychoactive drugs with anxiolytic, sedative, skeletal muscle relaxant and amnestic properties. Recently triazolo-benzodiazepines have been also described as potent and highly selective protein interaction inhibitors of bromodomain and extra-terminal (BET) proteins, a family of transcriptional co-regulators that play a key role in cancer cell survival and proliferation, but the requirements for high affinity interaction of this compound class with bromodomains has not been described. Here we provide insight into the structure–activity relationship (SAR) and selectivity of this versatile scaffold. In addition, using high resolution crystal structures we compared the binding mode of a series of benzodiazepine (BzD) and related triazolo-benzotriazepines (BzT) derivatives including clinically approved drugs such as alprazolam and midazolam. Our analysis revealed the importance of the 1-methyl triazolo ring system for BET binding and suggests modifications for the development of further high affinity bromodomain inhibitors.	Mar 2012
I03-Macromolecular Crystallography	Small-Molecule Inhibition of BRDT for Male Contraception Martin M. Matzuk , Michael R. Mckeown , Panagis Filippakopoulos , Qinglei Li , Lang Ma , Julio E. Agno , Madeleine E. Lemieux , Sarah Picaud , Richard N. Yu , Jun Qi , Stefan Knapp , James E. Bradner Cell 150 (4), 673 - 684 DOI: 10.1016/j.cell.2012.06.045 PMID: 22901802 Diamond Proposal Number(s): [443] Open Access Show Abstract ▼ Abstract: A pharmacologic approach to male contraception remains a longstanding challenge in medicine. Toward this objective, we explored the spermatogenic effects of a selective small-molecule inhibitor (JQ1) of the bromodomain and extraterminal (BET) subfamily of epigenetic reader proteins. Here, we report potent inhibition of the testis-specific member BRDT, which is essential for chromatin remodeling during spermatogenesis. Biochemical and crystallographic studies confirm that occupancy of the BRDT acetyl-lysine binding pocket by JQ1 prevents recognition of acetylated histone H4. Treatment of mice with JQ1 reduced seminiferous tubule area, testis size, and spermatozoa number and motility without affecting hormone levels. Although JQ1-treated males mate normally, inhibitory effects of JQ1 evident at the spermatocyte and round spermatid stages cause a complete and reversible contraceptive effect. These data establish a new contraceptive that can cross the blood:testis boundary and inhibit bromodomain activity during spermatogenesis, providing a lead compound targeting the male germ cell for contraception.	Aug 2012
I04-Macromolecular Crystallography	PFI-1, a highly selective protein interaction inhibitor, targeting BET bromodomains S. Picaud , D. Da Costa , A. Thanasopoulou , P. Filippakopoulos , P. V. Fish , M. Philpott , O. Fedorov , P. Brennan , M. E. Bunnage , D. R. Owen , J. E. Bradner , P. Taniere , B. O'Sullivan , S. Muller , J. Schwaller , T. Stankovic , S. Knapp Cancer Research 73 (11), 3336 - 3346 DOI: 10.1158/0008-5472.CAN-12-3292 PMID: 23576556 Diamond Proposal Number(s): [8421] Show Abstract ▼ Abstract: Bromo and extra terminal (BET) proteins (BRD2, BRD3, BRD4, and BRDT) are transcriptional regulators required for efficient expression of several growth promoting and antiapoptotic genes as well as for cell-cycle progression.	May 2013
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation–π interaction Timothy P. C. Rooney , Panagis Filippakopoulos , Oleg Fedorov , Sarah Picaud , Wilian A. Cortopassi , Duncan A. Hay , Sarah Martin , Anthony Tumber , Catherine M. Rogers , Martin Philpott , Minghua Wang , Amber L. Thompson , Tom D. Heightman , David C. Pryde , Andrew Cook , Robert S. Paton , Susanne Müller , Stefan Knapp , Paul E. Brennan , Stuart J. Conway Angewandte Chemie International Edition 53 (24), 6126 - 6130 DOI: 10.1002/anie.201402750 PMID: 24821300 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation–? interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.	Jun 2014
I02-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Discovery and optimization of small-molecule ligands for the CBP/p300 bromodomains Duncan A. Hay , Oleg Fedorov , Sarah Martin , Dean C. Singleton , Cynthia Tallant Blanco , Christopher Wells , Sarah Picaud , Martin Philpott , Octovia P. Monteiro , Catherine M. Rogers , Stuart J. Conway , Timothy P. C. Rooney , Anthony Tumber , Clarence Yapp , Panagis Filippakopoulos , Mark E. Bunnage , Susanne Müller , S Knapp , Christopher J. Schofield , Paul E. Brennan Journal Of The American Chemical Society 136 (26), 9308 - 9319 DOI: 10.1021/ja412434f Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: Small-molecule inhibitors that target bromodomains outside of the bromodomain and extra-terminal (BET) sub-family are lacking. Here, we describe highly potent and selective ligands for the bromodomain module of the human lysine acetyl transferase CBP/p300, developed from a series of 5-isoxazolyl-benzimidazoles. Our starting point was a fragment hit, which was optimized into a more potent and selective lead using parallel synthesis employing Suzuki couplings, benzimidazole-forming reactions, and reductive aminations. The selectivity of the lead compound against other bromodomain family members was investigated using a thermal stability assay, which revealed some inhibition of the structurally related BET family members. To address the BET selectivity issue, X-ray crystal structures of the lead compound bound to the CREB binding protein (CBP) and the first bromodomain of BRD4 (BRD4(1)) were used to guide the design of more selective compounds. The crystal structures obtained revealed two distinct binding modes. By varying the aryl substitution pattern and developing conformationally constrained analogues, selectivity for CBP over BRD4(1) was increased. The optimized compound is highly potent (Kd = 21 nM) and selective, displaying 40-fold selectivity over BRD4(1). Cellular activity was demonstrated using fluorescence recovery after photo-bleaching (FRAP) and a p53 reporter assay. The optimized compounds are cell-active and have nanomolar affinity for CBP/p300; therefore, they should be useful in studies investigating the biological roles of CBP and p300 and to validate the CBP and p300 bromodomains as therapeutic targets.	Jul 2014
I03-Macromolecular Crystallography	Selective targeting of the BRG/PB1 bromodomains impairs embryonic and trophoblast stem cell maintenance O. Fedorov , J. Castex , C. Tallant Blanco , D. R. Owen , S. Martin , M. Aldeghi , O. Monteiro , P. Filippakopoulos , S. Picaud , J. D. Trzupek , B. S. Gerstenberger , C. Bountra , D. Willmann , C. Wells , M. Philpott , C. Rogers , P. C. Biggin , P. E. Brennan , M. E. Bunnage , R. Schule , Thomas Gunther , Stefan Knapp , Susanne Muller Science Advances 1, e1500723 - e1500723 DOI: 10.1126/sciadv.1500723 PMID: 26702435 Open Access Show Abstract ▼ Abstract: Mammalian SWI/SNF [also called Brg/Brahma-associated factors (BAFs)] are evolutionarily conserved chromatin-remodeling complexes regulating gene transcription programs during development and stem cell differentiation. BAF complexes contain an ATP (adenosine 5′-triphosphate)–driven remodeling enzyme (either BRG1 or BRM) and multiple protein interaction domains including bromodomains, an evolutionary conserved acetyl lysine–dependent protein interaction motif that recruits transcriptional regulators to acetylated chromatin. We report a potent and cell active protein interaction inhibitor, PFI-3, that selectively binds to essential BAF bromodomains. The high specificity of PFI-3 was achieved on the basis of a novel binding mode of a salicylic acid head group that led to the replacement of water molecules typically maintained in other bromodomain inhibitor complexes. We show that exposure of embryonic stem cells to PFI-3 led to deprivation of stemness and deregulated lineage specification. Furthermore, differentiation of trophoblast stem cells in the presence of PFI-3 was markedly enhanced. The data present a key function of BAF bromodomains in stem cell maintenance and differentiation, introducing a novel versatile chemical probe for studies on acetylation-dependent cellular processes controlled by BAF remodeling complexes.	Nov 2015
I04-Macromolecular Crystallography	Generation of a selective small molecule inhibitor of the CBP/P300 bromodomain for leukemia therapy S. Picaud , O. Fedorov , A. Thanasopoulou , K. Leonards , K. Jones , J. Meier , H. Olzscha , O. Monteiro , S. Martin , M. Philpott , A. Tumber , Panagis Filippakopoulos , C. Yapp , C. Wells , K. H. Che , A. Bannister , S. Robson , U. Kumar , N. Parr , K. Lee , D. Lugo , P. Jeffrey , S. Taylor , M. L. Vecellio , C. Bountra , P. E. Brennan , A. O' Mahony , S. Velichko , S. Muller , D. Hay , D. L. Daniels , M. Urh , N. B. La Thangue , T. Kouzarides , R. Prinjha , J. Schwaller , S. Knapp Cancer Research 75, 5106 - 5119 DOI: 10.1158/0008-5472.CAN-15-0236 Diamond Proposal Number(s): [6391] Open Access Show Abstract ▼ Abstract: The histone acetyltransferases CBP/p300 are involved in recurrent leukemia-associated chromosomal translocations and are key regulators of cell growth. Therefore, efforts to generate inhibitors of CBP/p300 are of clinical value. We developed a specific and potent acetyl-lysine competitive protein–protein interaction inhibitor, I-CBP112, that targets the CBP/p300 bromodomains. Exposure of human and mouse leukemic cell lines to I-CBP112 resulted in substantially impaired colony formation and induced cellular differentiation without significant cytotoxicity. I-CBP112 significantly reduced the leukemia-initiating potential of MLL-AF9+ acute myeloid leukemia cells in a dose-dependent manner in vitro and in vivo. Interestingly, I-CBP112 increased the cytotoxic activity of BET bromodomain inhibitor JQ1 as well as doxorubicin. Collectively, we report the development and preclinical evaluation of a novel, potent inhibitor targeting CBP/p300 bromodomains that impairs aberrant self-renewal of leukemic cells. The synergistic effects of I-CBP112 and current standard therapy (doxorubicin) as well as emerging treatment strategies (BET inhibition) provide new opportunities for combinatorial treatment of leukemia and potentially other cancers. Cancer Res; 75(23); 5106–19. ©2015 AACR.	Nov 2015
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Promiscuous targeting of bromodomains by bromosporine identifies BET proteins as master regulators of primary transcription response in leukemia Sarah Picaud , Katharina Leonards , Jean-Philippe Lambert , Oliver Dovey , Christopher Wells , Oleg Fedorov , Octovia Monteiro , Takao Fujisawa , Chen-Yi Wang , Hannah Lingard , Cynthia Tallant , Nikzad Nikbin , Lucie Guetzoyan , Richard Ingham , Steven V. Ley , Paul Brennan , Susanne Muller , Anastasia Samsonova , A.-C. Gingras , Juerg Schwaller , George Vassiliou , Stefan Knapp , Panagis Filippakopoulos Science Advances 2, e1600760 - e1600760 DOI: 10.1126/sciadv.1600760 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: Bromodomains (BRDs) have emerged as compelling targets for cancer therapy. The development of selective and potent BET (bromo and extra-terminal) inhibitors and their significant activity in diverse tumor models have rapidly translated into clinical studies and have motivated drug development efforts targeting non-BET BRDs. However, the complex multidomain/subunit architecture of BRD protein complexes complicates predictions of the consequences of their pharmacological targeting. To address this issue, we developed a promiscuous BRD inhibitor [bromosporine (BSP)] that broadly targets BRDs (including BETs) with nanomolar affinity, creating a tool for the identification of cellular processes and diseases where BRDs have a regulatory function. As a proof of principle, we studied the effects of BSP on leukemic cell lines known to be sensitive to BET inhibition and found, as expected, strong antiproliferative activity. Comparison of the modulation of transcriptional profiles by BSP after a short exposure to the inhibitor resulted in a BET inhibitor signature but no significant additional changes in transcription that could account for inhibition of other BRDs. Thus, nonselective targeting of BRDs identified BETs, but not other BRDs, as master regulators of context-dependent primary transcription response.	Oct 2016
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Multivalent histone and DNA engagement by a PHD/BRD/PWWP triple reader cassette recruits ZMYND8 to k14ac-rich chromatin Pavel Savitsky , Tobias Krojer , Takao Fujisawa , Jean-Philippe Lambert , Sarah Picaud , Chen-Yi Wang , Erin K. Shanle , Krzysztof Krajewski , Hans Friedrichsen , Alexander Kanapin , Colin Goding , Matthieu Schapira , Anastasia Samsonova , Brian D. Strahl , Anne-Claude Gingras , Panagis Filippakopoulos Cell Reports 17, 2724 - 2737 DOI: 10.1016/j.celrep.2016.11.014 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: Elucidation of interactions involving DNA and histone post-translational-modifications (PTMs) is essential for providing insights into complex biological functions. Reader assemblies connected by flexible linkages facilitate avidity and increase affinity; however, little is known about the contribution to the recognition process of multiple PTMs because of rigidity in the absence of conformational flexibility. Here, we resolve the crystal structure of the triple reader module (PHD-BRD-PWWP) of ZMYND8, which forms a stable unit capable of simultaneously recognizing multiple histone PTMs while presenting a charged platform for association with DNA. Single domain disruptions destroy the functional network of interactions initiated by ZMYND8, impairing recruitment to sites of DNA damage. Our data establish a proof of principle that rigidity can be compensated by concomitant DNA and histone PTM interactions, maintaining multivalent engagement of transient chromatin states. Thus, our findings demonstrate an important role for rigid multivalent reader modules in nucleosome binding and chromatin function.	Dec 2016

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