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

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	8-Substituted O6-Cyclohexylmethylguanine CDK2 Inhibitors: Using Structure-Based Inhibitor Design to Optimize an Alternative Binding Mode Benoit Carbain , David J. Paterson , Elizabeth Anscombe , Allyson J. Campbell , Celine Cano , Aude Echalier , Jane A. Endicott , Bernard T. Golding , Karen Haggerty , Ian R. Hardcastle , Philip J. Jewsbury , David R. Newell , Martin E. M. Noble , Celine Roche , Lan Z. Wang , Roger J. Griffin Journal Of Medicinal Chemistry 57 (1), 56 - 70 DOI: 10.1021/jm401555v PMID: 24304238 Show Abstract ▼ Abstract: Evaluation of the effects of purine C-8 substitution within a series of CDK1/2-selective O6-cyclohexylmethylguanine derivatives revealed that potency decreases initially with increasing size of the alkyl substituent. Structural analysis showed that C-8 substitution is poorly tolerated, and to avoid unacceptable steric interactions, these compounds adopt novel binding modes. Thus, 2-amino-6-cyclohexylmethoxy-8-isopropyl-9H-purine adopts a “reverse” binding mode where the purine backbone has flipped 180°. This provided a novel lead chemotype from which we have designed more potent CDK2 inhibitors using, in the first instance, quantum mechanical energy calculations. Introduction of an ortho-tolyl or ortho-chlorophenyl group at the purine C-8 position restored the potency of these “reverse” binding mode inhibitors to that of the parent 2-amino-6-cyclohexylmethoxy-9H-purine. By contrast, the corresponding 8-(2-methyl-3-sulfamoylphenyl)-purine derivative exhibited submicromolar CDK2-inhibitory activity by virtue of engineered additional interactions with Asp86 and Lys89 in the reversed binding mode, as confirmed by X-ray crystallography.	Dec 2013
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design Yaw Sing Tan , Judith Reeks , Christopher J. Brown , Dawn Thean , Fernando Jose Ferrer Gago , Tsz Ying Yuen , Eunice Tze Leng Goh , Xue Er Cheryl Lee , Claire E. Jennings , Thomas L. Joseph , Rajamani Lakshminarayanan , David P. Lane , Martin E. M. Noble , Chandra S. Verma The Journal Of Physical Chemistry Letters 7, 3452 - 3457 DOI: 10.1021/acs.jpclett.6b01525 Diamond Proposal Number(s): [9948] Show Abstract ▼ Abstract: Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.	Sep 2016
	CCP 4 i 2: the new graphical user interface to the CCP 4 program suite Liz Potterton , Jon Agirre , Charles Ballard , Kevin Cowtan , Eleanor Dodson , Phil R. Evans , Huw T. Jenkins , Ronan Keegan , Eugene Krissinel , Kyle Stevenson , Andrey Lebedev , Stuart J. Mcnicholas , Robert A. Nicholls , Martin Noble , Navraj S. Pannu , Christian Roth , George Sheldrick , Pavol Skubak , Johan Turkenburg , Ville Uski , Frank Von Delft , David Waterman , Keith Wilson , Martyn Winn , Marcin Wojdyr Acta Crystallographica Section D Structural Biology 74, 68 - 84 DOI: 10.1107/S2059798317016035 Open Access Show Abstract ▼ Abstract: The CCP4 (Collaborative Computational Project, Number 4) software suite for macromolecular structure determination by X-ray crystallography groups brings together many programs and libraries that, by means of well established conventions, interoperate effectively without adhering to strict design guidelines. Because of this inherent flexibility, users are often presented with diverse, even divergent, choices for solving every type of problem. Recently, CCP4 introduced CCP4i2, a modern graphical interface designed to help structural biologists to navigate the process of structure determination, with an emphasis on pipelining and the streamlined presentation of results. In addition, CCP4i2 provides a framework for writing structure-solution scripts that can be built up incrementally to create increasingly automatic procedures.	Feb 2018
I02-Macromolecular Crystallography	CDK1 structures reveal conserved and unique features of the essential cell cycle CDK Nicholas R. Brown , Svitlana Korolchuk , Mathew P. Martin , Will A. Stanley , Rouslan Moukhametzianov , Martin Noble , Jane A. Endicott Nature Communications 6 DOI: 10.1038/ncomms7769 PMID: 25864384 Open Access Show Abstract ▼ Abstract: CDK1 is the only essential cell cycle CDK in human cells and is required for successful completion of M-phase. It is the founding member of the CDK family and is conserved across all eukaryotes. Here we report the crystal structures of complexes of CDK1–Cks1 and CDK1–cyclin B–Cks2. These structures confirm the conserved nature of the inactive monomeric CDK fold and its ability to be remodelled by cyclin binding. Relative to CDK2–cyclin A, CDK1–cyclin B is less thermally stable, has a smaller interfacial surface, is more susceptible to activation segment dephosphorylation and shows differences in the substrate sequence features that determine activity. Both CDK1 and CDK2 are potential cancer targets for which selective compounds are required. We also describe the first structure of CDK1 bound to a potent ATP-competitive inhibitor and identify aspects of CDK1 structure and plasticity that might be exploited to develop CDK1-selective inhibitors.	Nov 2015
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Comparative structural and functional studies of 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile CDK9 inhibitors suggest the basis for isotype selectivity Alison Hole , Sonja Baumli , Hao Shao , Shenhua Shi , Chris Pepper , Peter M. Fischer , Shudong Wang , Jane Endicott , Martin Noble Journal Of Medicinal Chemistry 56 (3) DOI: 10.1021/jm301495v PMID: 23252711 Open Access Show Abstract ▼ Abstract: Cyclin-dependent kinase 9/cyclin T, the protein kinase heterodimer that constitutes positive transcription elongation factor b, is a well-validated target for treatment of several diseases, including cancer and cardiac hypertrophy. In order to aid inhibitor design and rationalize the basis for CDK9 selectivity, we have studied the CDK-binding properties of six different members of a 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series that bind to both CDK9/cyclin T and CDK2/cyclin A. We find that for a given CDK, the melting temperature of a CDK/cyclin/inhibitor complex correlates well with inhibitor potency, suggesting that differential scanning fluorimetry (DSF) is a useful orthogonal measure of inhibitory activity for this series. We have used DSF to demonstrate that the binding of these compounds is independent of the presence or absence of the C-terminal tail region of CDK9, unlike the binding of the CDK9-selective inhibitor 5,6-dichlorobenzimidazone-1-?-d-ribofuranoside (DRB). Finally, on the basis of 11 cocrystal structures bound to CDK9/cyclin T or CDK2/cyclin A, we conclude that selective inhibition of CDK9/cyclin T by members of the 4-(thiazol-5-yl)-2-(phenylamino)pyrimidine-5-carbonitrile series results from the relative malleability of the CDK9 active site rather than from the formation of specific polar contacts.	Dec 2012
I04-1-Macromolecular Crystallography (fixed wavelength)	Cyclin-Dependent Kinase (CDK) Inhibitors; Structure-Activity Relationships and Insights into the CDK-2 Selectivity of 6-Substituted 2-Arylaminopurines Christopher R Coxon , Elizabeth Anscombe , Suzannah Jane Harnor , Mathew P. Martin , Benoit Jean-pierre Carbain , Bernard Thomas Golding , Ian Robert Hardcastle , Lisa K Harlow , Svitlana Korolchuk , Christopher J. Matheson , David R. Newell , Martin E. M. Noble , Mangaleswaran Sivaprakasam , Susan J. Tudhope , David M. Turner , Lan-zhen Wang , Stephen R Wedge , Christopher Wong , Roger John Griffin , Jane A. Endicott , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6b01254 Diamond Proposal Number(s): [13587] Show Abstract ▼ Abstract: Purines and related heterocycles substituted at C-2 with 4’-sulfamoylanilino and at C-6 with a variety of groups have been synthesized with the aim of achieving selectivity of binding to CDK2 over CDK1. 6-Substituents that favour competitive inhibition at the ATP binding site of CDK2 were identified and typically exhibited 10-80-fold greater inhibition of CDK2 compared to CDK1. Most impressive was 4-((6-([1,1'-biphenyl]-3-yl)-9H-purin-2-yl)amino) benzenesulfonamide (73) that exhibited high potency towards CDK2 (IC50 0.044 μM), but was ~ 2000-fold less active towards CDK1 (IC50 86 μM). This compound is therefore a useful tool for studies of cell cycle regulation. Crystal structures of inhibitor-kinase complexes showed that the inhibitor stabilizes a glycine-rich loop conformation that shapes the ATP ribose binding pocket, and that is preferred in CDK2, but has not been observed in CDK1. This aspect of the active site may be exploited for the design of inhibitors that distinguish between CDK1 and CDK2.	Dec 2016
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition Daniel J. Wood , Svitlana Korolchuk , Natalie J. Tatum , Lan-zhen Wang , Jane A. Endicott , Martin E. M. Noble , Mathew P. Martin Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.10.015 Diamond Proposal Number(s): [18598, 13587] Open Access Show Abstract ▼ Abstract: Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.	Nov 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Identification and Characterization of an Irreversible Inhibitor of CDK2 Elizabeth Anscombe , Elisa Meschini , Regina Mora-vidal , Mathew p. Martin , David Staunton , Matthis Geitmann , U. helena Danielson , Will a. Stanley , Lan z. Wang , Tristan Reuillon , Bernard t. Golding , Celine Cano , David r. Newell , Martin Noble , Stephen r. Wedge , Jane a. Endicott , Roger j. Griffin Chemistry & Biology 22 (9), 1159 - 1164 DOI: 10.1016/j.chembiol.2015.07.018 PMID: 26320860 Open Access Show Abstract ▼ Abstract: Irreversible inhibitors that modify cysteine or lysine residues within a protein kinase ATP binding site offer, through their distinctive mode of action, an alternative to ATP-competitive agents. 4-((6-(Cyclohexylmethoxy)-9H-purin-2-yl)amino)benzenesulfonamide (NU6102) is a potent and selective ATP-competitive inhibitor of CDK2 in which the sulfonamide moiety is positioned close to a pair of lysine residues. Guided by the CDK2/NU6102 structure, we designed 6-(cyclohexylmethoxy)-N-(4-(vinylsulfonyl)phenyl)-9H-purin-2-amine (NU6300), which binds covalently to CDK2 as shown by a co-complex crystal structure. Acute incubation with NU6300 produced a durable inhibition of Rb phosphorylation in SKUT-1B cells, consistent with it acting as an irreversible CDK2 inhibitor. NU6300 is the first covalent CDK2 inhibitor to be described, and illustrates the potential of vinyl sulfones for the design of more potent and selective compounds.	Sep 2015
	Identification of a novel ligand for the ATAD2 bromodomain with selectivity over BRD4 through a fragment growing approach Duncan C. Miller , Mathew P. Martin , Santosh Adhikari , Alfie Brennan , Jane A. Endicott , Bernard T. Golding , Ian R. Hardcastle , Amy Heptinstall , Stephen Hobson , Claire Jennings , Lauren Molyneux , Yvonne Ng , Stephen R. Wedge , Martin Noble , Celine Cano Organic & Biomolecular Chemistry 21 DOI: 10.1039/C8OB00099A Show Abstract ▼ Abstract: ATAD2 is an ATPase that is overexpressed in a variety of cancers and associated with a poor patient prognosis. This protein has been suggested to function as a cofactor for a range of transcription factors, including the proto-oncogene MYC and the androgen receptor. ATAD2 comprises an ATPase domain, implicated in chromatin remodelling, and a bromodomain which allows it to interact with acetylated histone tails. Dissection of the functional roles of these two domains would benefit from the availability of selective, cell-permeable pharmacological probes. An in silico evaluation of the 3D structures of various bromodomains suggested that developing small molecule ligands for the bromodomain of ATAD2 is likely to be challenging, although recent reports have shown that ATAD2 bromodomain ligands can be identified. We report a structure-guided fragment-based approach to identify lead compounds for ATAD2 bromodomain inhibitor development. Our findings indicate that the ATAD2 bromodomain can accommodate fragment hits (Mr < 200) that yield productive structure–activity relationships, and structure-guided design enabled the introduction of selectivity over BRD4.	Feb 2018
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Identification of a novel orally bioavailable ERK5 inhibitor with selectivity over p38α and BRD4 Stephanie Myers , Duncan C. Miller , Lauren Molyneux , Mercedes Arasta , Ruth H. Bawn , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Tim Hammonds , Ian R. Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , David R. Newell , Paul J. Owen , Leon C. Pang , Tristan Reuillon , Laurent J. M. Rigoreau , Huw Thomas , Julie A. Tucker , Lan-zhen Wang , Ai-ching Wong , Martin E. M. Noble , Stephen R. Wedge , Celine Cano European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.057 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: Extracellular regulated kinase 5 (ERK5) signalling has been implicated in driving a number of cellular phenotypes including endothelial cell angiogenesis and tumour cell motility. Novel ERK5 inhibitors were identified using high throughput screening, with a series of pyrrole-2-carboxamides substituted at the 4-position with an aroyl group being found to exhibit IC50 values in the micromolar range, but having no selectivity against p38α MAP kinase. Truncation of the N-substituent marginally enhanced potency (∼3-fold) against ERK5, but importantly attenuated inhibition of p38α. Systematic variation of the substituents on the aroyl group led to the selective inhibitor 4-(2-bromo-6-fluorobenzoyl)-N-(pyridin-3-yl)-1H-pyrrole-2-carboxamide (IC50 0.82 μM for ERK5; IC50 > 120 μM for p38α). The crystal structure (PDB 5O7I) of this compound in complex with ERK5 has been solved. This compound was orally bioavailable and inhibited bFGF-driven Matrigel plug angiogenesis and tumour xenograft growth. The selective ERK5 inhibitor described herein provides a lead for further development into a tool compound for more extensive studies seeking to examine the role of ERK5 signalling in cancer and other diseases.	May 2019

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