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36 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Rapid covalent-probe discovery by electrophile-fragment screening Efrat Resnick , Anthony Bradley , Jinrui Gan , Alice Douangamath , Tobias Krojer , Ritika Sethi , Paul P. Geurink , Anthony Aimon , Gabriel Amitai , Dom Bellini , James Bennett , Michael Fairhead , Oleg Fedorov , Ronen Gabizon , Jin Gan , Jingxu Guo , Alexander Plotnikov , Nava Reznik , Gian Filippo Ruda , Laura Diaz-saez , Verena M. Straub , Tamas Szommer , Srikannathasan Velupillai , Daniel Zaidman , Yanling Zhang , Alun R. Coker , Christopher G. Dowson , Haim Barr , Chu Wang , Kilian V. M. Huber , Paul E. Brennan , Huib Ovaa , Frank Von Delft , Nir London Journal Of The American Chemical Society DOI: 10.1021/jacs.9b02822 Show Abstract ▼ Abstract: Covalent probes can display unmatched potency, selectivity and duration of action; however, their discovery is challenging. In principle, fragments that can irreversibly bind their target can overcome the low affinity that limits reversible fragment screening, but such electrophilic fragments were considered non-selective and were rarely screened. We hypothesized that mild electrophiles might overcome the selectivity challenge and constructed a library of 993 mildly electrophilic fragments. We characterized this library by a new high-throughput thiol-reactivity assay and screened them against ten cysteine-containing proteins. Highly reactive and promiscuous fragments were rare and could be easily eliminated. By contrast, we found hits for most targets. Combining our approach with high-throughput crystallography allowed rapid progression to potent and selective probes for two enzymes, the deubiquitinase OTUB2 and the pyrophosphatase NUDT7. No inhibitors were previously known for either. This study highlights the potential of electrophile-fragment screening as a practical and efficient tool for covalent-ligand discovery.	May 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays Yann-vai Le Bihan , Rachel M. Lanigan , Butrus Atrash , Mark G. Mclaughlin , Srikannathasan Velupillai , Andrew G. Malcolm , Katherine S. England , Gian Filippo Ruda , N. Yi Mok , Anthony Tumber , Kathy Tomlin , Harry Saville , Erald Shehu , Craig Mcandrew , Leanne Carmichael , James M. Bennett , Fiona Jeganathan , Paul Eve , Adam Donovan , Angela Hayes , Francesca Wood , Florence I. Raynaud , Oleg Fedorov , Paul Brennan , Rosemary Burke , Rob Van Montfort , Olivia W. Rossanese , Julian Blagg , Vassilios Bavetsias European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.041 Diamond Proposal Number(s): [20145] Open Access Show Abstract ▼ Abstract: Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, the conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggest that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.	May 2019
	Targeting the small GTPase superfamily through their regulatory proteins Janine L. Gray , Frank Von Delft , Paul Brennan Angewandte Chemie International Edition DOI: 10.1002/anie.201900585 Show Abstract ▼ Abstract: The Ras superfamily of small GTPases are guanine nucleotide dependent switches essential for numerous cellular processes. Mutations or dysregulation of these proteins are associated with many diseases, but unsuccessful attempts to target the small GTPases directly have resulted in them being classed as ‘undruggable’. The GTP dependent signaling of these proteins is controlled by their regulators; guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and in the Rho and Rab subfamilies, guanine nucleotide dissociation inhibitors (GDIs). This review covers the recent small molecule and biologics strategies to target the small GTPases through their regulators. It seeks to critically re‐evaluate recent chemical biology practice, such as the presence of PAINs motifs and the cell‐based readout using compounds that are weakly potent or of unknown specificity. It highlights the vast scope of potential approaches for targeting the small GTPases in the future through their regulatory proteins.	Mar 2019
I03-Macromolecular Crystallography	An activity-based probe targeting non-catalytic, highly conserved amino acid residues within bromodomains Melissa D'ascenzio , Kathryn M. Pugh , Rebecca Konietzny , Georgina Berridge , Cynthia Tallant , Shaima Hashem , Octovia Monteiro , Jason R. Thomas , Markus Schirle , Stefan Knapp , Brian Marsden , Oleg Fedorov , Chas Bountra , Benedikt M. Kessler , Paul E. Brennan Angewandte Chemie International Edition 58, 1007 - 1012 DOI: 10.1002/anie.201807825 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: Bromodomain‐containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl‐lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule‐based approach to covalently modify recombinant and endogenous bromodomain‐containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in‐gel visualization and pull‐down of the desired bromodomains.	Jan 2019
I04-Macromolecular Crystallography	Design, synthesis and characterization of covalent kdm5 inhibitors Saleta Vazquez-rodriguez , Miranda Wright , Catherine M. Rogers , Adam P. Cribbs , Srikannathasan Velupillai , Martin Philpott , Henry Lee , James E. Dunford , Kilian V. M. Huber , Matthew B. Robers , James D. Vasta , Marie-laetitia Thezenas , Sarah Bonham , Benedikt Kessler , James Bennett , Oleg Fedorov , Florence Raynaud , Adam Donovan , Julian Blagg , Vassilios Bavetsias , Udo Oppermann , Chas Bountra , Akane Kawamura , Paul E. Brennan Angewandte Chemie International Edition 58, 515 - 519 DOI: 10.1002/anie.201810179 Diamond Proposal Number(s): [15433] Open Access Show Abstract ▼ Abstract: Histone lysine demethylases (KDMs) are involved in the dynamic regulation of gene expression and they play a critical role in several biological processes. Achieving selectivity over the different KDMs has been a major challenge for KDM inhibitor development. Here we report potent and selective KDM5 covalent inhibitors designed to target cysteine residues only present in the KDM5 sub‐family. The covalent binding to the targeted proteins was confirmed by MS and time‐dependent inhibition. Additional competition assays show that compounds were non 2‐OG competitive. Target engagement and ChIP‐seq analysis showed that the compounds inhibited the KDM5 members in cells at nano‐ to micromolar levels and induce a global increase of the H3K4me3 mark at transcriptional start sites.	Jan 2019
I04-Macromolecular Crystallography	A structure-based approach towards identification of inhibitory fragments for eleven-nineteen-leukemia protein (ENL) David Heidenreich , Moses Moustakim , Jurema Schmidt , Daniel Merk , Paul E. Brennan , Oleg Fedorov , Apirat Chaikuad , Stefan Knapp Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b01457 Diamond Proposal Number(s): [105433] Show Abstract ▼ Abstract: Lysine acetylation is an epigenetic mark that is principally recognized by bromodomains and recently structurally diverse YEATS domains also emerged as readers of lysine acetyl/acylations. Here we present a crystallography-based strategy and the discovery of fragments binding to the ENL YEATS domain, a potential drug target. Crystal structures combined with synthetic efforts led to the identification of a sub-micromolar binder, providing first starting points for the development of chemical probes for this reader domain family.	Nov 2018
	Discovery of an MLLT1/3 YEATS domain chemical probe Moses Moustakim , Thomas Christott , Octovia P. Monteiro , James Bennett , Charline Giroud , Jennifer Ward , Catherine M. Rogers , Paul Smith , Ioanna Panagakou , Laura Diaz-saez , Suet Ling Felce , Vicki Gamble , Carina Gileadi , Nadia Halidi , David Heidenreich , Apirat Chaikuad , Stefan Knapp , Kilian V. M. Huber , Gillian Farnie , Jag Heer , Nenad Manevski , Gennady Poda , Rima Al-awar , Darren J. Dixon , Paul E. Brennan , Oleg Fedorov Angewandte Chemie International Edition 57, 16302 - 16307 DOI: 10.1002/anie.v57.50 Show Abstract ▼ Abstract: YEATS domain (YD) containing proteins are an emerging class of epigenetic targets in drug discovery. Dysregulation of these modified lysine‐binding proteins has been linked to the onset and progression of cancers. We herein report the discovery and characterisation of the first small‐molecule chemical probe, SGC‐iMLLT, for the YD of MLLT1 (ENL/YEATS1) and MLLT3 (AF9/YEATS3). SGC‐iMLLT is a potent and selective inhibitor of MLLT1/3–histone interactions. Excellent selectivity over other human YD proteins (YEATS2/4) and bromodomains was observed. Furthermore, our probe displays cellular target engagement of MLLT1 and MLLT3. The first small‐molecule X‐ray co‐crystal structures with the MLLT1 YD are also reported. This first‐in‐class probe molecule can be used to understand MLLT1/3‐associated biology and the therapeutic potential of small‐molecule YD inhibitors.	Oct 2018
	Discovery of a novel allosteric inhibitor scaffold for polyadenosine-diphosphate-ribose polymerase 14 (PARP14) macrodomain 2 Moses Moustakim , Kerstin Riedel , Marion Schuller , Andrè P. Gehring , Octovia P. Monteiro , Sarah P. Martin , Oleg Fedorov , Jag Heer , Darren J. Dixon , Jonathan M. Elkins , Stefan Knapp , Franz Bracher , Paul E. Brennan Bioorganic & Medicinal Chemistry DOI: 10.1016/j.bmc.2018.03.020 Show Abstract ▼ Abstract: The polyadenosine-diphosphate-ribose polymerase 14 (PARP14) has been implicated in DNA damage response pathways for homologous recombination. PARP14 contains three (ADP ribose binding) macrodomains (MD) whose exact contribution to overall PARP14 function in pathology remains unclear. A medium throughput screen led to the identification of N-(2(-9H-carbazol-1-yl)phenyl)acetamide (GeA-69, 1) as a novel allosteric PARP14 MD2 (second MD of PARP14) inhibitor. We herein report medicinal chemistry around this novel chemotype to afford a sub-micromolar PARP14 MD2 inhibitor. This chemical series provides a novel starting point for further development of PARP14 chemical probes.	Mar 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Identifying small molecule binding sites for epigenetic proteins at domain-domain interfaces Paul Brennan , David Bowkett , Romain Talon , Cynthia Tallant , Chris Schofield , Gordon Bruton , Frank Von Delft , Stefan Knapp Chemmedchem DOI: 10.1002/cmdc.201800030 Show Abstract ▼ Abstract: Epigenetics is of rapidly growing field in drug discovery. Of particular interest is the role of post‐translational modifications to histone and the proteins that read, write, and erase such modifications. The development of inhibitors for reader domains has focused on single domains. One of the major difficulties of designing inhibitors for reader domains, is that with the notable exception of bromodomains, they tend not to possess a well enclosed binding site amenable to small molecule inhibition. As many of the proteins in epigenetic regulation have multiple domains there are opportunities for designing inhibitors that bind at a domain‐domain interface which provide a more suitable interaction pocket. Examination of X‐ray structures of multiple domains involved in recognizing and modifying post‐translational histone marks using the SiteMap algorithm identified potential binding sites at domain‐domain interfaces. For the tandem plant homeodomain‐bromodomain of SP100C, a potential inter‐domain site identified computationally was validated experimentally by the discovery of ligands by X‐ray crystallographic fragment screening.	Mar 2018
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Halogen-aromatic π-interactions modulate inhibitor residence time Christina Heroven , Victoria Georgi , Gaurav K. Ganotra , Paul E. Brennan , Finn Wolfreys , Rebecca C. Wade , Amaury E. Fernández-montalván , Apirat Chaikuad , Stefan Knapp Angewandte Chemie International Edition DOI: 10.1002/anie.201801666 Diamond Proposal Number(s): [10619] Show Abstract ▼ Abstract: Prolonged drug residence times may result in longer lasting drug efficacy, improved pharmacodynamic properties and "kinetic selectivity" over off-targets with fast drug dissociation rates. However, few strategies have been elaborated to rationally modulate drug residence time and thereby to integrate this key property into the drug development process. Here, we show that the interaction between a halogen moiety on an inhibitor and an aromatic residue in the target protein can significantly increase inhibitor residence time. By using the interaction of the serine/threonine kinase haspin with 5-iodotubercidin (5-iTU) derivatives as a model for an archetypal active state (type I) kinase-inhibitor binding mode, we demonstrate that inhibitor residence times markedly increase with the size and polarizability of the halogen atom. This key interaction is dependent on the interactions with an aromatic residue in the gatekeeper position and we observe this interaction in other kinases with an aromatic gatekeeper residue. We provide a detailed mechanistic characterization of the halogen-aromatic π interactions in the haspin-inhibitor complexes by means of kinetic, thermodynamic, and structural measurements along with binding energy calculations. Since halogens are frequently used in drugs and aromatic residues are often present in the binding sites of proteins, our results provide a compelling rationale for introducing aromatic-halogen interactions to prolong drug-target residence times.	Mar 2018

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