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33 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	Identification of unprecedented ATP-competitive choline kinase inhibitors Francesca Quartieri , Marcella Nesi , Nilla R. Avanzi , Daniela Borghi , Elena Casale , Emiliana Corti , Ulisse Cucchi , Daniele Donati , Marina Fasolini , Eduard R. Felder , Arturo Galvani , Maria L. Giorgini , Antonio Lomolino , Maria Menichincheri , Christian Orrenius , Claudia Perrera , Stefania Re Depaolini , Federico Riccardi-Sirtori , Enea Salsi , Antonella Isacchi , Paola Gnocchi Bioorganic & Medicinal Chemistry Letters 51 DOI: 10.1016/j.bmcl.2021.128310 Diamond Proposal Number(s): [26586] Show Abstract ▼ Abstract: In this article we describe the identification of unprecedented ATP-competitive ChoKα inhibitors starting from initial hit NMS-P830 that binds to ChoKα in an ATP concentration-dependent manner. This result is confirmed by the co-crystal structure of NMS-P830 in complex with Δ75-ChoKα. NMS-P830 is able to inhibit ChoKα in cells resulting in the reduction of intracellular phosphocholine formation. A structure-based medicinal chemistry program resulted in the identification of selective compounds that have good biochemical activity, solubility and metabolic stability and are suitable for further optimization. The ChoKα inhibitors disclosed in this article demonstrate for the first time the possibility to inhibit ChoKα with ATP-competitive compounds.	Nov 2021
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding John Liddle , Andrew C. Pearce , Christopher Arico-Muendel , Svetlana Belyanskaya , Andrew Brewster , Murray Brown , Chun-Wa Chung , Alexis Denis , Nerina Dodic , Anthony Dossang , Peter Eddershaw , Diana Klimaszewska , Imran Haq , Duncan S. Holmes , Alistair Jagger , Toral Jakhria , Emilie Jigorel , Ken Lind , Jeff Messer , Margaret Neu , Allison Olszewski , Riccardo Ronzoni , James Rowedder , Martin Rüdiger , Steve Skinner , Kathrine J. Smith , Lionel Trottet , Iain Uings , Zhengrong Zhu , James A. Irving , David A. Lomas Bioorganic & Medicinal Chemistry Letters 41 DOI: 10.1016/j.bmcl.2021.127973 Diamond Proposal Number(s): [23853, 17201] Show Abstract ▼ Abstract: α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.	Jun 2021
I04-1-Macromolecular Crystallography (fixed wavelength)	Free energy perturbation in the design of EED ligands as inhibitors of polycomb repressive complex 2 (PRC2) methyltransferase Daniel H. O' Donovan , Clare Gregson , Martin J. Packer , Ryan Greenwood , Kurt G. Pike , Sameer Kawatkar , Andrew Bloecher , James Robinson , Jon Read , Erin Code , Jessie Hao-Ru Hsu , Minhui Shen , Haley Woods , Peter Barton , Shaun Fillery , Beth Williamson , Philip B. Rawlins , Sharan K. Bagal Bioorganic & Medicinal Chemistry Letters 39 DOI: 10.1016/j.bmcl.2021.127904 Show Abstract ▼ Abstract: Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.	May 2021
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] 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] Open Access 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

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