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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
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Development of a selective dual discoidin domain receptor (DDR)/p38 kinase chemical probe Sandra Röhm , Benedict-Tilman Berger , Martin Schröder , Deep Chatterjee , Sebastian Mathea , Andreas C. Joerger , Daniel M. Pinkas , Joshua C. Bufton , Amelie Tjaden , Lohitesh Kovooru , Mark Kudolo , Christian Pohl , Alex N. Bullock , Susanne Müller , Stefan Laufer , Stefan Knapp Journal Of Medicinal Chemistry 64, 13451 - 13474 DOI: 10.1021/acs.jmedchem.1c00868 Show Abstract ▼ Abstract: Discoidin domain receptors 1 and 2 (DDR1/2) play a central role in fibrotic disorders, such as renal and pulmonary fibrosis, atherosclerosis, and various forms of cancer. Potent and selective inhibitors, so-called chemical probe compounds, have been developed to study DDR1/2 kinase signaling. However, these inhibitors showed undesired activity on other kinases such as the tyrosine protein kinase receptor TIE or tropomyosin receptor kinases, which are related to angiogenesis and neuronal toxicity. In this study, we optimized our recently published p38 mitogen-activated protein kinase inhibitor 7 toward a potent and cell-active dual DDR/p38 chemical probe and developed a structurally related negative control. The structure-guided design approach used provided insights into the P-loop folding process of p38 and how targeting of non-conserved amino acids modulates inhibitor selectivity. The developed and comprehensively characterized DDR/p38 probe, 30 (SR-302), is a valuable tool for studying the role of DDR kinase in normal physiology and in disease development.	Sep 2021
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
I03-Macromolecular Crystallography	Development, optimization and structure–activity relationships of covalent-reversible JAK3 inhibitors based on a tricyclic imidazo[5,4-d]pyrrolo[2,3-b]pyridine scaffold Michael Forster , Apirat Chaikuad , Teodor Dimitrov , Eva Döring , Julia Holstein , Benedict-Tilman Berger , Matthias Gehringer , Kamran Ghoreschi , Susanne Müller , Stefan Knapp , Stefan A. Laufer Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00571 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: Janus kinases are major drivers of immune signaling and have been the focus of anti-inflammatory drug discovery for more than a decade. Because of the invariable co-localization of JAK1 and JAK3 at cytokine receptors, the question if selective JAK3 inhibition is sufficient to effectively block downstream signaling has been highly controversial. Recently, we discovered the covalent-reversible JAK3 inhibitor FM-381 (23) featuring high isoform and kinome selectivity. Crystallography revealed that this inhibitor induces an unprecedented binding pocket by interactions of a nitrile substituent with arginine residues in JAK3. Herein we describe detailed structure activity relationships necessary for induction of the arginine pocket and the impact of this structural change on potency, isoform selectivity and efficacy in cellular models. Furthermore, we evaluated the stability of this novel inhibitor class in in vitro metabolic assays and were able to demonstrate an adequate stability of key compound 23 for in vivo use.	May 2018
I03-Macromolecular Crystallography	Design of a chemical probe for the Bromodomain and Plant Homeodomain Finger-containing (BRPF) family of proteins Niall Igoe , Elliott D. Bayle , Cynthia Tallant , Oleg Fedorov , Julia C. Meier , Pavel Savitsky , Catherine Rogers , Yannick Morias , Sarah Scholze , Helen Boyd , Danen Cunoosamy , David M. Andrews , Anne Cheasty , Paul E. Brennan , Susanne Müller , Stefan Knapp , Paul V. Fish Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.7b00611 Show Abstract ▼ Abstract: The bromodomain and plant homeodomain finger-containing (BRPF) family are scaffolding proteins important for the recruitment of histone acetyltransferases of the MYST family to chromatin. Here, we describe NI-57 (16) as new pan-BRPF chemical probe of the bromodomain (BRD) of the BRPFs. Inhibitor 16 preferentially bound the BRD of BRPF1 and BRPF2 over BRPF3, whereas binding to BRD9 was weaker. Compound 16 has excellent selectivity over nonclass IV BRD proteins. Target engagement of BRPF1B and BRPF2 with 16 was demonstrated in nanoBRET and FRAP assays. The binding of 16 to BRPF1B was rationalized through an X-ray cocrystal structure determination, which showed a flipped binding orientation when compared to previous structures. We report studies that show 16 has functional activity in cellular assays by modulation of the phenotype at low micromolar concentrations in both cancer and inflammatory models. Pharmacokinetic data for 16 was generated in mouse with single dose administration showing favorable oral bioavailability.	Jul 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
I04-1-Macromolecular Crystallography (fixed wavelength)	Highly selective inhibition of histone demethylases by de novo macrocyclic peptides Akane Kawamura , Martin Münzel , Tatsuya Kojima , Clarence Yapp , Bhaskar Bhushan , Yuki Goto , Anthony Tumber , Takayuki Katoh , Oliver N. F. King , Toby Passioura , Louise J. Walport , Stephanie B. Hatch , Sarah Madden , Susanne Müller , Paul E. Brennan , Rasheduzzaman Chowdhury , Richard J. Hopkinson , Hiroaki Suga , Christopher J. Schofield Nature Communications 8 DOI: 10.1038/ncomms14773 Diamond Proposal Number(s): [1230, 9306] Open Access Show Abstract ▼ Abstract: The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.	Apr 2017
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 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
I04-Macromolecular Crystallography	Development of selective CBP/P300 benzoxazepine bromodomain inhibitors Tobias A. Popp , Cynthia Tallant , Catherine Rogers , Oleg Fedorov , Paul E. Brennan , Susanne Müller , Stefan Knapp , Franz Bracher Journal Of Medicinal Chemistry 59, 8889 - 8912 DOI: 10.1021/acs.jmedchem.6b00774 Show Abstract ▼ Abstract: CBP (CREB (cAMP responsive element binding protein) binding protein (CREBBP)) and P300 (adenovirus E1A-associated 300 kDa protein) are two closely related histone acetyltransferases (HATs) that play a key role in the regulation of gene transcription. Both proteins contain a bromodomain flanking the HAT catalytic domain that is important for the targeting of CBP/P300 to chromatin and which offeres an opportunity for the development of protein–protein interaction inhibitors. Here we present the development of CBP/P300 bromodomain inhibitors with 2,3,4,5-tetrahydro-1,4-benzoxazepine backbone, an N-acetyl-lysine mimetic scaffold that led to the recent development of the chemical probe I-CBP112. We present comprehensive SAR of this inhibitor class as well as demonstration of cellular on target activity of the most potent and selective inhibitor TPOP146, which showed 134 nM affinity for CBP with excellent selectivity over other bromodomains.	Oct 2016

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