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26 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	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
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	Discovery of potent and selective Spleen Tyrosine Kinase inhibitors for the topical treatment of inflammatory skin disease Michael D. Barker , John Liddle , Francis L. Atkinson , David Matthew Wilson , Marion C. Dickson , Cesar Ramirez-molina , Huw Lewis , Rob P. Davis , Donald O. Somers , Margarete Neu , Emma Jones , Robert Watson Bioorganic & Medicinal Chemistry Letters 28, 3458 - 3462 DOI: 10.1016/j.bmcl.2018.09.022 Show Abstract ▼ Abstract: The discovery and lead optimisation of a novel series of SYK inhibitors is described. These were optimised for SYK potency and selectivity against Aurora B. Compounds were profiled in a human skin penetration study to identify a suitable candidate molecule for pre-clinical development. Compound 44 (GSK2646264) was selected for progression and is currently in Phase I clinical trials.	Nov 2018
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
I04-Macromolecular Crystallography	Design, synthesis and evaluation of potent and selective inhibitors of mono-(ADP-ribosyl)transferases PARP10 and PARP14 Jacob Holechek , Robert Lease , Ann-gerd Thorsell , Tobias Karlberg , Caitlin Mccadden , Ryan Grant , Abby Keen , Evan Callahan , Herwig Schüler , Dana Ferraris Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2018.04.056 Diamond Proposal Number(s): [15806] Show Abstract ▼ Abstract: A series of diaryl ethers were designed and synthesized to discern the structure activity relationships against the two closely related mono-(ADP-ribosyl)transferases PARP10 and PARP14. Structure activity studies identified 8b as a sub-micromolar inhibitor of PARP10 with ∼15-fold selectivity over PARP14. In addition, 8k and 8m were discovered to have sub-micromolar potency against PARP14 and demonstrated moderate selectivity over PARP10. A crystal structure of the complex of PARP14 and 8b shows binding of the compound in a novel hydrophobic pocket and explains both potency and selectivity over other PARP family members. In addition, 8b, 8k and 8m also demonstrate selectivity over PARP1. Together, this study identified novel, potent and metabolically stable derivatives to use as chemical probes for these biologically interesting therapeutic targets.	May 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Activation loop targeting strategy for design of receptor-interacting protein kinase 2 (RIPK2) inhibitors Chalada Suebsuwong , Daniel M. Pinkas , Soumya S. Ray , Joshua C. Bufton , Bing Dai , Alex N. Bullock , Alexei Degterev , Gregory D. Cuny Bioorganic & Medicinal Chemistry Letters DOI: 10.1016/j.bmcl.2018.01.044 Diamond Proposal Number(s): [15433] Open Access Show Abstract ▼ Abstract: Development of selective kinase inhibitors remains a challenge due to considerable amino acid sequence similarity among family members particularly in the ATP binding site. Targeting the activation loop might offer improved inhibitor selectivity since this region of kinases is less conserved. However, the strategy presents difficulties due to activation loop flexibility. Herein, we report the design of receptor-interacting protein kinase 2 (RIPK2) inhibitors based on pan-kinase inhibitor regorafenib that aim to engage basic activation loop residues Lys169 or Arg171. We report development of CSR35 that displayed >10-fold selective inhibition of RIPK2 versus VEGFR2, the target of regorafenib. A co-crystal structure of CSR35 with RIPK2 revealed a resolved activation loop with an ionic interaction between the carboxylic acid installed in the inhibitor and the side-chain of Lys169. Our data provides principle feasibility of developing activation loop targeting type II inhibitors as a complementary strategy for achieving improved selectivity.	Jan 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	6-Substituted quinolines as RORγt inverse agonists J. Kent Barbay , Maxwell D. Cummings , Marta Abad , Glenda Castro , Kevin D. Kreutter , David A. Kummer , Umar Maharoof , Cynthia Milligan , Rachel Nishimura , Joan Pierce , Celine Schalk-hihi , John Spurlino , Virginia M. Tanis , Maud Urbanski , Hariharan Venkatesan , Aihua Wang , Craig Woods , Ronald Wolin , Xiaohua Xue , James P. Edwards , Anne M. Fourie , Kristi Leonard Bioorganic & Medicinal Chemistry Letters 27, 5277 - 5283 DOI: 10.1016/j.bmcl.2017.10.027 Show Abstract ▼ Abstract: We identified 6-substituted quinolines as modulators of the retinoic acid receptor-related orphan receptor gamma t (RORγt). The synthesis of this class of RORγt modulators is reported, and optimization of the substituents at the quinoline 6-position that produced compounds with high affinity for the receptor is detailed. This effort identified molecules that act as potent, full inverse agonists in a RORγt-driven cell-based reporter assay. The X-ray crystal structures of two full inverse agonists from this chemical series bound to the RORγt ligand binding domain are disclosed, and we highlight the interaction of a hydrogen-bond acceptor on the 6-position substituent of the inverse agonist with Glu379:NH as a conserved binding contact.	Dec 2017

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