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30 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	Covalent inactivation of Mycobacterium thermoresistibile inosine-5′-monophosphate dehydrogenase (IMPDH) Ana Trapero , Angela Pacitto , Daniel Shiu-hin Chan , Chris Abell , Tom L. Blundell , David B. Ascher , Anthony G. Coyne Bioorganic & Medicinal Chemistry Letters 30 DOI: 10.1016/j.bmcl.2019.126792 Diamond Proposal Number(s): [14043] Open Access Show Abstract ▼ Abstract: Inosine-5′-monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme involved in nucleotide biosynthesis. Because of its critical role in purine biosynthesis, IMPDH is a drug design target for immunosuppressive, anticancer, antiviral and antimicrobial chemotherapy. In this study, we use mass spectrometry and X-ray crystallography to show that the inhibitor 6-Cl-purine ribotide forms a covalent adduct with the Cys-341 residue of Mycobacterium thermoresistibile IMPDH.	Jan 2020
I04-Macromolecular Crystallography	Design and development of a series of borocycles as selective, covalent kallikrein 5 inhibitors Ann L. Walker , Alexis Denis , Ryan P. Bingham , Anne Boulliot , Emma V. Edgar , Alan Ferrie , Duncan S. Holmes , Alain Laroze , John Liddle , Marie-helene Fouchet , Alexandre Moquette , Pam Nassau , Andrew C. Pearce , Oxana Polyakova , Kathrine J. Smith , Pamela Thomas , James H. Thorpe , Lionel Trottet , Yichen Wang , Alain Hovnanian Bioorganic & Medicinal Chemistry Letters 29 DOI: 10.1016/j.bmcl.2019.126675 Diamond Proposal Number(s): [5799] Show Abstract ▼ Abstract: The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.	Oct 2019
I03-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Scaffold-hopping identifies furano[2,3-d]pyrimidine amides as potent Notum inhibitors Benjamin N. Atkinson , David Steadman , William Mahy , Yuguang Zhao , James Sipthorp , Elliott D. Bayle , Fredrik Svensson , George Papageorgiou , Fiona Jeganathan , Sarah Frew , Amy Monaghan , Magda Bictash , E. Yvonne Jones , Paul V. Fish Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.126751 Diamond Proposal Number(s): [14744] Show Abstract ▼ Abstract: The carboxylesterase Notum is a key negative regulator of the Wnt signaling pathway by mediating the depalmitoleoylation of Wnt proteins. Our objective was to discover potent small molecule inhibitors of Notum suitable for exploring the regulation of Wnt signaling in the central nervous system. Scaffold-hopping from thienopyrimidine acids 1 and 2, supported by X-ray structure determination, identified 3-methylimidazolin-4-one amides 20-24 as potent inhibitors of Notum with activity across three orthogonal assay formats (biochemical, extra-cellular, occupancy). A preferred example 24 demonstrated good stability in mouse microsomes and plasma, and cell permeability in the MDCK-MDR1 assay albeit with modest P-gp mediated efflux. Pharmacokinetic studies with 24 were performed in vivo in mouse with single oral administration of 24 showing good plasma exposure and reasonable CNS penetration. We propose that 24 is a new chemical tool suitable for cellular studies to explore the fundamental biology of Notum.	Oct 2019
I02-Macromolecular Crystallography	Type 2 inhibitor leads of human tropomyosin receptor kinase (hTrkA) Govindan Subramanian , Scott J. Bowen , Yaqi Zhu , Nicole Roush , Theresa Zachary , Christopher Javens , Tracey Williams , Ann Janssen , Andrea Gonzales Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.126624 Show Abstract ▼ Abstract: In silico virtual screening using the ligand-based ROCS approach and the commercially purchasable compound collection from the ZINC database resulted in the identification of distinctly different and novel acetamide core frameworks with series representatives 1a and 2a exhibiting nanomolar affinity in the kinase domain only hTrkA HTRF biochemical assay. Additional experimental validation using the Caliper technology with either the active or inactive kinase conditions demonstrated the leads, 1a and 2a, to preferentially bind the kinase inactive state. X-ray structural analysis of the kinase domain of hTrkA…1a/2a complexes confirmed the kinase, bind the inhibitor leads in the inactive state and to exhibit a type 2 binding mode with the DFG-out and αC-helix out conformation. The leads also demonstrated sub-micromolar activity in the full length hTrkA cell-based assay and selectivity against the closely related hTrkB isoform. However, the poor microsomal stability and permeability of the leads is suggestive of a multiparametric lead optimization effort requirement for further progression.	Aug 2019
I03-Macromolecular Crystallography	Tool inhibitors and assays to interrogate the biology of the TRAF2 and NCK interacting kinase Jon Read , Iain T. Collie , Michelle Nguyen-mccarty , Christopher Lucaj , James Robinson , Leslie Conway , Jayanta Mukherjee , Eileen Mccall , Gerard Donohoe , Elizabeth Flavell , Karolina Peciak , Juli Warwicker , Carly Dix , Bernard G. Van Den Hoven , Andrew Madin , Dean G. Brown , Stephen Moss , Stephen J. Haggarty , Nicholas J. Brandon , Roland W. Bürli Bioorganic & Medicinal Chemistry Letters 29, 1962 - 1967 DOI: 10.1016/j.bmcl.2019.05.032 Show Abstract ▼ Abstract: The TRAF2 and NCK interacting kinase (TNIK) has been proposed to play a role in cytoskeletal organization and synaptic plasticity and has been linked, among others, to neurological disorders. However, target validation efforts for TNIK have been hampered by the limited kinase selectivity of small molecule probes and possible functional compensation in mouse models. Both issues are at least in part due to its close homology to the kinases MINK1 (or MAP4K6) and MAP4K4 (or HGK). As part of our interest in validating TNIK as a therapeutic target for neurological diseases, we set up a panel of biochemical and cellular assays, which are described herein. We then examined the activity of known amino-pyridine-based TNIK inhibitors (1, 3) and prepared structurally very close analogs that lack the ability to inhibit the target. We also developed a structurally orthogonal, naphthyridine-based TNIK inhibitor (9) and an inactive control molecule of the same chemical series. These validated small-molecule probes will enable dissection of the function of TNIK family in the context of human disease biology.	Aug 2019
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of a class of highly potent Janus Kinase 1/2 (JAK1/2) inhibitors demonstrating effective cell-based blockade of IL-13 signaling Mark Zak , Emily J. Hanan , Patrick Lupardus , David G. Brown , Colin Robinson , Michael Siu , Joseph P. Lyssikatos , F. Anthony Romero , Guiling Zhao , Terry Kellar , Rohan Mendonca , Nicholas C. Ray , Simon C. Goodacre , Peter H. Crackett , Neville Mclean , Christopher A. Hurley , Po-wai Yuen , Yun-xing Cheng , Xiongcai Liu , Marya Liimatta , Pawan Bir Kohli , Jim Nonomiya , Gary Salmon , Gerry Buckley , Julia Lloyd , Paul Gibbons , Nico Ghilardi , Jane R. Kenny , Adam Johnson Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.04.008 Diamond Proposal Number(s): [5069, 14629] Show Abstract ▼ Abstract: Disruption of interleukin-13 (IL-13) signaling with large molecule antibody therapies has shown promise in diseases of allergic inflammation. Given that IL-13 recruits several members of the Janus Kinase family (JAK1, JAK2, and TYK2) to its receptor complex, JAK inhibition may offer an alternate small molecule approach to disrupting IL-13 signaling. Herein we demonstrate that JAK1 is likely the isoform most important to IL-13 signaling. Structure-based design was then used to improve the JAK1 potency of a series of previously reported JAK2 inhibitors. The ability to impede IL-13 signaling was thereby significantly improved, with the best compounds exhibiting single digit nM IC50’s in cell-based assays dependent upon IL-13 signaling. Appropriate substitution was further found to influence inhibition of a key off-target, LRRK2. Finally, the most potent compounds were found to be metabolically labile, which makes them ideal scaffolds for further development as topical agents for IL-13 mediated diseases of the lungs and skin (for example asthma and atopic dermatitis, respectively).	Apr 2019
I03-Macromolecular Crystallography I23-Long wavelength MX	Structure-guided design of antibacterials that allosterically inhibit DNA gyrase Reema K. Thalji , Kaushik Raha , Daniele Andreotti , Anna Checchia , Haifeng Cui , Giovanni Meneghelli , Roberto Profeta , Federica Tonelli , Simona Tommasi , Tania Bakshi , Brian T. Donovan , Alison Howells , Shruti Jain , Christopher Nixon , Geoffrey Quinque , Lynn Mccloskey , Benjamin D. Bax , Margarete Neu , Pan F. Chan , Robert A. Stavenger Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.03.029 Diamond Proposal Number(s): [1195] Show Abstract ▼ Abstract: A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.	Mar 2019
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome Gemma V. White , Emma V. Edgar , Duncan S. Holmes , Xiao Qing Lewell , John Liddle , Oxana Polyakova , Kathrine J. Smith , James H. Thorpe , Ann L. Walker , Yichen Wang , Robert J. Young , Alain Hovnanian Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.01.020 Diamond Proposal Number(s): [5799] Show Abstract ▼ Abstract: Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10–100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.	Jan 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure-based design, synthesis and biological evaluation of a novel series of isoquinolone and pyrazolo[4,3-c]pyridine inhibitors of fascin 1 as potential anti-metastatic agents Stuart Francis , Daniel Croft , Alexander W. Schuettelkopf , Charles Parry , Angelo Pugliese , Ken Cameron , Sophie Claydon , Martin Drysdale , Claire Gardner , Andrea Gohlke , Gillian Goodwin , Christopher H. Gray , Jennifer Konczal , Laura Mcdonald , Mokdad Mezna , Andrew Pannifer , Nikki Paul , Laura Machesky , Heather Mckinnon , Justin Bower Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2019.01.035 Diamond Proposal Number(s): [6683, 8659, 11651] Open Access Show Abstract ▼ Abstract: Fascin is an actin binding and bundling protein that is not expressed in normal epithelial tissues but overexpressed in a variety of invasive epithelial tumors. It has a critical role in cancer cell metastasis by promoting cell migration and invasion. Here we report the crystal structures of fascin in complex with a series of novel and potent inhibitors. Subsequent structure-based elaboration of this and related compounds enabled the development of a series with nanomolar affinities for fascin, good physicochemical properties and the ability to inhibit fascin-mediated bundling of filamentous actin. These compounds provide promising starting points for fascin-targeted anti-metastatic therapies.	Jan 2019
I04-Macromolecular Crystallography	Development and characterization of a CNS-penetrant benzhydryl hydroxamic acid class IIa histone deacetylase inhibitor Christopher A. Luckhurst , Omar Aziz , Vahri Beaumont , Roland W. Bürli , Perla Breccia , Michel C. Maillard , Alan F. Haughan , Marieke Lamers , Phil Leonard , Kim L. Matthews , Gilles Raphy , Andrew J. Stott , Ignacio Munoz-sanjuan , Beth Thomas , Michael Wall , Grant Wishart , Dawn Yates , Celia Dominguez Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2018.11.009 Show Abstract ▼ Abstract: We have identified a potent, cell permeable and CNS penetrant class IIa histone deacetylase (HDAC) inhibitor 22, with >500-fold selectivity over class I HDACs (1,2,3) and ∼150-fold selectivity over HDAC8 and the class IIb HDAC6 isoform. Dose escalation pharmacokinetic analysis demonstrated that upon oral administration, compound 22 can reach exposure levels in mouse plasma, muscle and brain in excess of cellular class IIa HDAC IC50 levels for ∼8 h. Given the interest in aberrant class IIa HDAC function for a number of neurodegenerative, neuromuscular, cardiac and oncology indications, compound 22 (also known as CHDI-390576) provides a selective and potent compound to query the role of class IIa HDAC biology, and the impact of class IIa catalytic site occupancy in vitro and in vivo.	Nov 2018

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