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

Instruments / Technical Area	Publication Details	Published
	Target 2035 – update on the quest for a probe for every protein Susanne Müller , Suzanne Ackloo , Arij Al Chawaf , Bissan Al-Lazikani , Albert Antolin , Jonathan B. Baell , Hartmut Beck , Shaunna Beedie , Ulrich A. K. Betz , Gustavo Arruda Bezerra , Paul E. Brennan , David Brown , Peter J. Brown , Alex N. Bullock , Adrian J. Carter , Apirat Chaikuad , Mathilde Chaineau , Alessio Ciulli , Ian Collins , Jan Dreher , David Drewry , Kristina Edfeldt , Aled M. Edwards , Ursula Egner , Stephen V. Frye , Stephen M. Fuchs , Matthew D. Hall , Ingo V. Hartung , Alexander Hillisch , Stephen H. Hitchcock , Evert Homan , Natarajan Kannan , James R. Kiefer , Stefan Knapp , Milka Kostic , Stefan Kubicek , Andrew S. Leach , Sven Lindemann , Brian D. Marsden , Hisanori Matsui , Jordan L. Meier , Daniel Merk , Maurice Michel , Maxwell R. Morgan , Anke Mueller-Fahrnow , Dafydd R. Owen , Benjamin G. Perry , Saul H. Rosenberg , Kumar Singh Saikatendu , Matthieu Schapira , Cora Scholten , Sujata Sharma , Anton Simeonov , Michael Sundström , Giulio Superti-Furga , Matthew H. Todd , Claudia Tredup , Masoud Vedadi , Frank Von Delft , Timothy M. Willson , Georg E. Winter , Paul Workman , Cheryl H. Arrowsmith Rsc Medicinal Chemistry 17 DOI: 10.1039/D1MD00228G Open Access Show Abstract ▼ Abstract: Twenty years after the publication of the first draft of the human genome, our knowledge of the human proteome is still fragmented. The challenge of translating the wealth of new knowledge from genomics into new medicines is that proteins, and not genes, are the primary executers of biological function. Therefore, much of how biology works in health and disease must be understood through the lens of protein function. Accordingly, a subset of human proteins has been at the heart of research interests of scientists over the centuries, and we have accumulated varying degrees of knowledge about approximately 65% of the human proteome. Nevertheless, a large proportion of proteins in the human proteome (∼35%) remains uncharacterized, and less than 5% of the human proteome has been successfully targeted for drug discovery. This highlights the profound disconnect between our abilities to obtain genetic information and subsequent development of effective medicines. Target 2035 is an international federation of biomedical scientists from the public and private sectors, which aims to address this gap by developing and applying new technologies to create by year 2035 chemogenomic libraries, chemical probes, and/or biological probes for the entire human proteome.	Dec 2021
I02-Macromolecular Crystallography	Discovery of a chemical tool inhibitor targeting the bromodomains of TRIM24 and BRPF James Bennett , Oleg Fedorov , Cynthia Tallant , Octovia Monteiro , Julia Meier , Vicky Gamble , Pavel Savitsky , Graciela A Nunez-Alonso , Bernard Haendler , Catherine Rogers , Paul E. Brennan , Susanne Müller , Stefan Knapp Journal Of Medicinal Chemistry 27 (9) DOI: 10.1021/acs.jmedchem.5b00458 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: TRIM24 is a transcriptional regulator as well as an E3 ubiquitin ligase. It is overexpressed in diverse tumors, and high expression levels have been linked to poor prognosis in breast cancer patients. TRIM24 contains a PHD/bromodomain offering the opportunity to develop protein interaction inhibitors that target this protein interaction module. Here we identified potent acetyl-lysine mimetic benzimidazolones TRIM24 bromodomain inhibitors. The best compound of this series is a selective BRPF1B/ TRIM24 dual inhibitor that bound with a KD of 137 and 222 nM, respectively, but exerted good selectivity over other bromodomains. Cellular activity of the inhibitor was demonstrated using FRAP assays as well as cell viability data.	May 2015
I02-Macromolecular Crystallography	Potent and selective KDM5 inhibitor stops cellular demethylation of H3K4me3 at transcription start sites and proliferation of mm1s myeloma cells Anthony Tumber , Andrea Nuzzi , Edward S. Hookway , Stephanie B. Hatch , Srikannathasan Velupillai , Catrine Johansson , Akane Kawamura , Pavel Savitsky , Clarence Yapp , Aleksandra Szykowska , Na Wu , Chas Bountra , Claire Strain-Damerell , Nicola A. Burgess-Brown , Gian Filippo Ruda , Oleg Fedorov , Shonagh Munro , Katherine S. England , Radoslaw P. Nowak , Christopher J. Schofield , Nicholas B. La Thangue , Charlotte Pawlyn , Faith Davies , Gareth Morgan , Nick Athanasou , Susanne Müller , Udo Oppermann , Paul E. Brennan Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.02.006 Open Access Show Abstract ▼ Abstract: Methylation of lysine residues on histone tail is a dynamic epigenetic modification that plays a key role in chromatin structure and gene regulation. Members of the KDM5 (also known as JARID1) sub-family are 2-oxoglutarate (2-OG) and Fe2+-dependent oxygenases acting as histone 3 lysine 4 trimethyl (H3K4me3) demethylases, regulating proliferation, stem cell self-renewal, and differentiation. Here we present the characterization of KDOAM-25, an inhibitor of KDM5 enzymes. KDOAM-25 shows biochemical half maximal inhibitory concentration values of <100 nM for KDM5A-D in vitro, high selectivity toward other 2-OG oxygenases sub-families, and no off-target activity on a panel of 55 receptors and enzymes. In human cell assay systems, KDOAM-25 has a half maximal effective concentration of ∼50 μM and good selectivity toward other demethylases. KDM5B is overexpressed in multiple myeloma and negatively correlated with the overall survival. Multiple myeloma MM1S cells treated with KDOAM-25 show increased global H3K4 methylation at transcriptional start sites and impaired proliferation.	Mar 2017
I02-Macromolecular Crystallography	Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains Léa Bouché , Clara D. Christ , Stephan Siegel , Amaury E. Fernández-Montalván , Simon J. Holton , Oleg Fedorov , Antonius Ter Laak , Tatsuo Sugawara , Detlef Stöckigt , Cynthia Tallant , James Bennett , Octovia Monteiro , Laura Díaz-Sáez , Paulina Siejka , Julia Meier , Vera Pütter , Jörg Weiske , Susanne Müller , Kilian V. M. Huber , Ingo V. Hartung , Bernard Haendler Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00306 Diamond Proposal Number(s): [15558, 10619] Show Abstract ▼ Abstract: Bromodomains (BD) are readers of lysine acetylation marks present in numerous proteins associated with chromatin. Here we describe a dual inhibitor of the bromodomain and PHD finger (BRPF) family member BRPF2 and the TATA box binding protein-associated factors TAF1 and TAF1L. These proteins are found in large chromatin complexes and play important roles in transcription regulation. The substituted benzoisoquinolinedione series was identified by high-throughput screening, and subsequent structure–activity relationship optimization allowed generation of low nanomolar BRPF2 BD inhibitors with strong selectivity against BRPF1 and BRPF3 BDs. In addition, a strong inhibition of TAF1/TAF1L BD2 was measured for most derivatives. The best compound of the series was BAY-299, which is a very potent, dual inhibitor with an IC50 of 67 nM for BRPF2 BD, 8 nM for TAF1 BD2, and 106 nM for TAF1L BD2. Importantly, no activity was measured for BRD4 BDs. Furthermore, cellular activity was evidenced using a BRPF2– or TAF1–histone H3.3 or H4 interaction assay.	May 2017
I02-Macromolecular Crystallography	WNT activates the AAK1 kinase to promote clathrin-mediated endocytosis of LRP6 and establish a negative feedback loop Megan J. Agajanian , Matthew P. Walker , Alison D. Axtman , Roberta R. Ruela-De-Sousa , D. Stephen Serafin , Alex D. Rabinowitz , David M. Graham , Meagan B. Ryan , Tigist Tamir , Yuko Nakamichi , Melissa V. Gammons , James M. Bennett , Rafael M. Counago , David H. Drewry , Jonathan M. Elkins , Carina Gileadi , Opher Gileadi , Paulo H. Godoi , Nirav Kapadia , Susanne Müller , André S. Santiago , Fiona J. Sorrell , Carrow I. Wells , Oleg Fedorov , Timothy M. Willson , William J. Zuercher , Michael B. Major Cell Reports 26, 79 - 93.e8 DOI: 10.1016/j.celrep.2018.12.023 Open Access Show Abstract ▼ Abstract: β-Catenin-dependent WNT signal transduction governs development, tissue homeostasis, and a vast array of human diseases. Signal propagation through a WNT-Frizzled/LRP receptor complex requires proteins necessary for clathrin-mediated endocytosis (CME). Paradoxically, CME also negatively regulates WNT signaling through internalization and degradation of the receptor complex. Here, using a gain-of-function screen of the human kinome, we report that the AP2 associated kinase 1 (AAK1), a known CME enhancer, inhibits WNT signaling. Reciprocally, AAK1 genetic silencing or its pharmacological inhibition using a potent and selective inhibitor activates WNT signaling. Mechanistically, we show that AAK1 promotes clearance of LRP6 from the plasma membrane to suppress the WNT pathway. Time-course experiments support a transcription-uncoupled, WNT-driven negative feedback loop; prolonged WNT treatment drives AAK1-dependent phosphorylation of AP2M1, clathrin-coated pit maturation, and endocytosis of LRP6. We propose that, following WNT receptor activation, increased AAK1 function and CME limits WNT signaling longevity.	Jan 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography	CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses Ariane Hammitzsch , Cynthia Tallant Blanco , Oleg Fedorov , Alison O’mahony , Paul E. Brennan , Duncan A. Hay , Fernando O. Martinez , M. Hussein Al-Mossawi , Jelle De Wit , Matteo Vecellio , Christopher Wells , Paul Wordsworth , Susanne Müller , Stefan Knapp , Paul Bowness Proceedings Of The National Academy Of Sciences 112 (34), 10768 - 10773 DOI: 10.1073/pnas.1501956112 Diamond Proposal Number(s): [8421] Show Abstract ▼ Abstract: Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.	Aug 2015
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
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure of cyclin G-associated kinase (GAK) trapped in different conformations using nanobodies Apirat Chaikuad , Tracy Keates , Cécile Vincke , Melanie Kaufholz , Michael Zenn , Bastian Zimmermann , Carlos Gutiérrez , Rong‑guang Zhang , Catherine Hatzos‑skintges , Andrzej Joachimiak , Serge Muyldermans , Friedrich w. Herberg , Stefan Knapp , Susanne Müller Biochemical Journal 459, 59 - 69 DOI: 10.1042/BJ20131399 PMID: 24438162 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: GAK (cyclin G-associated kinase) is a key regulator of clathrin-coated vesicle trafficking and plays a central role during development. Additionally, due to the unusually high plasticity of its catalytic domain, it is a frequent ‘off-target’ of clinical kinase inhibitors associated with respiratory side effects of these drugs. In the present paper, we determined the crystal structure of the GAK catalytic domain alone and in complex with specific single-chain antibodies (nanobodies). GAK is constitutively active and weakly associates in solution. The GAK apo structure revealed a dimeric inactive state of the catalytic domain mediated by an unusual activation segment interaction. Co-crystallization with the nanobody NbGAK_4 trapped GAK in a dimeric arrangement similar to the one observed in the apo structure, whereas NbGAK_1 captured the activation segment of monomeric GAK in a well-ordered conformation, representing features of the active kinase. The presented structural and biochemical data provide insight into the domain plasticity of GAK and demonstrate the utility of nanobodies to gain insight into conformational changes of dynamic molecules. In addition, we present structural data on the binding mode of ATP mimetic inhibitors and enzyme kinetic data, which will support rational inhibitor design of inhibitors to reduce the off-target effect on GAK.	Apr 2014
I02-Macromolecular Crystallography I04-Macromolecular Crystallography	Design of a biased potent small molecule inhibitor of the bromodomain and PHD finger-containing (BRPF) proteins suitable for cellular and in vivo studies Niall Igoe , Elliott D. Bayle , Oleg Fedorov , Cynthia Tallant , Pavel Savitsky , Catherine Rogers , Dafydd R. Owen , Gauri Deb , Tim C. P. Somervaille , David M. Andrews , Neil Jones , Anne Cheasty , Hamish Ryder , Paul E. Brennan , Susanne Müller , Stefan Knapp , Paul V. Fish Journal Of Medicinal Chemistry 60, 668 - 680 DOI: 10.1021/acs.jmedchem.6b01583 Show Abstract ▼ Abstract: The BRPF (bromodomain and PHD finger-containing) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Evaluation of the BRPF family as a potential drug target is at an early stage although there is an emerging understanding of a role in acute myeloid leukemia (AML). We report the optimization of fragment hit 5b to 13-d as a biased, potent inhibitor of the BRD of the BRPFs with excellent selectivity over nonclass IV BRD proteins. Evaluation of 13-d in a panel of cancer cell lines showed a selective inhibition of proliferation of a subset of AML lines. Pharmacokinetic studies established that 13-d had properties compatible with oral dosing in mouse models of disease (Fpo 49%). We propose that NI-42 (13-d) is a new chemical probe for the BRPFs suitable for cellular and in vivo studies to explore the fundamental biology of these proteins.	Jan 2017
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	LP99: discovery and synthesis of the first selective BRD7/9 bromodomain inhibitor Peter G. K. Clark , Lucas C. C. Vieira , Cynthia Tallant , Oleg Fedorov , Dean C. Singleton , Catherine M. Rogers , Octovia P. Monteiro , James M. Bennett , Roberta Baronio , Susanne Müller , Danette L. Daniels , Jacqui Méndez , Stefan Knapp , Paul E. Brennan , Darren J. Dixon Angewandte Chemie International Edition 54 (21), 6217 - 6221 DOI: 10.1002/anie.201501394 PMID: 25864491 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: The bromodomain-containing proteins BRD9 and BRD7 are part of the human SWI/SNF chromatin-remodeling complexes BAF and PBAF. To date, no selective inhibitor for BRD7/9 has been reported despite its potential value as a biological tool or as a lead for future therapeutics. The quinolone-fused lactam LP99 is now reported as the first potent and selective inhibitor of the BRD7 and BRD9 bromodomains. Development of LP99 from a fragment hit was expedited through balancing structure-based inhibitor design and biophysical characterization against tractable chemical synthesis: Complexity-building nitro-Mannich/lactamization cascade processes allowed for early structure–activity relationship studies whereas an enantioselective organocatalytic nitro-Mannich reaction enabled the synthesis of the lead scaffold in enantioenriched form and on scale. This epigenetic probe was shown to inhibit the association of BRD7 and BRD9 to acetylated histones in vitro and in cells. Moreover, LP99 was used to demonstrate that BRD7/9 plays a role in regulating pro-inflammatory cytokine secretion.	May 2015

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