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194 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2, 3, 4, 5, 6, 7, 8 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I24-Microfocus Macromolecular Crystallography	Structure-based drug discovery of...(HTL22562): a calcitonin gene-related peptide (CGRP) receptor antagonist for acute treatment of migraine Sarah J. Bucknell , Mark A. Ator , Alastair Brown , Jason Brown , Andrew Cansfield , Julie Cansfield , John Christopher , Miles Congreve , Gabriella Cseke , Francesca Deflorian , Christopher Jones , Jonathan S. Mason , Alistair O'brien , Gregory R. Ott , Mark Pickworth , Stacey Southall Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01003 Show Abstract ▼ Abstract: Structure-based drug design enabled the discovery of 8, HTL22562, a CGRP receptor antagonist. The structure of 8 complexed with the CGRP receptor was determined at 1.6 Å resolution. Compound 8 is a highly potent, selective, metabolically stable and soluble compound suitable for a range of administration routes that have the potential to provide rapid systemic exposures with resultant high levels of receptor coverage (e.g. subcutaneous). The low lipophilicity coupled with a low anticipated clinically efficacious plasma exposure for migraine also suggests a reduced potential for hepatotoxicity. These properties have led to 8 being taken forward as a clinical candidate for acute treatment of migraine.	Jun 2020
I02-Macromolecular Crystallography	Fragment-based discovery of pyrazolopyridones as JAK1 inhibitors with excellent subtype selectivity Bettina Borreschmidt Hansen , Tue Heesgaard Jepsen , Mogens Larsen , Rikke Sindet , Thomas Vifian , Mia Nørreskov Burhardt , Jens Larsen , Jimmi Gerner Seitzberg , Martin A. Carnerup , Anders Jerre , Christina Mølck , Paola Lovato , Sanjay Rai , Venkatarathnam Reddy Nasipireddy , Andreas Ritzén Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00359 Show Abstract ▼ Abstract: Herein, we report the discovery of a series of JAK1-selective kinase inhibitors with high potency and excellent JAK family subtype selectivity. A fragment screening hit 1 with a pyrazolopyridone core and a JAK1 bias was selected as the starting point for our fragment-based lead generation efforts. A two-stage strategy was chosen with the dual aims of improving potency and JAK1 selectivity: Optimization of the lipophilic ribose pocket-targeting substituent was followed by the introduction of a variety of P-loop-targeting functional groups. Combining the best moieties from both stages of the optimization afforded compound 40, which showed excellent potency and selectivity. Metabolism studies in vitro and in vivo together with an in vitro safety evaluation suggest that 40 may be a viable lead compound for the development of highly subtype-selective JAK1 inhibitors.	Jun 2020
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Mining the PDB for tractable cases where X-ray crystallography combined with fragment screens can be used to systematically design protein-protein inhibitors. Two test cases illustrated by IL1β-IL1R and p38α-TAB1 complexes Charlie Nichols , Joseph Ng , Annika Keshu , Geoff Kelly , Maria Rosaria Conte , Michael Stephen Marber , Franca Fraternali , Gian De Nicola Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00403 Diamond Proposal Number(s): [18781, 14320, 20574] Show Abstract ▼ Abstract: Nowadays it is possible to combine X-ray crystallography and fragment screening in a medium throughput fashion to chemically probe the surfaces used by proteins to interact and use the outcome of the screens to systematically design protein-protein inhibitors. To prove it we first performed a bioinformatics analysis of the Protein Data Bank protein complexes, which revealed over 400 cases where the crystal lattice of the target in the free form is such that large portions of the interacting surfaces are free from lattice contacts and therefore accessible to fragments during soaks. Among the tractable complexes identified, we then performed single fragment crystal screens on two particular interesting cases: the Il1β-ILR and p38α-TAB1 complexes. The result of the screens showed that fragments tend to bind in clusters, highlighting the small-molecule hotspots on the surface of the target protein. In most of the cases the hotspots overlapped with the binding sites of the interacting proteins.	Jun 2020
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Novel thienopyrimidine inhibitors of Leishmania N -myristoyltransferase with on-target activity in intracellular amastigotes Andrew S. Bell , Zhiyong Yu , Jennie A. Hutton , Megan H. Wright , James A. Brannigan , Daniel Paape , Shirley M. Roberts , Charlotte L. Sutherell , Markus Ritzefeld , Anthony Wilkinson , Deborah F Smith , Robin Leatherbarrow , Edward W. Tate Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00570 Diamond Proposal Number(s): [1221, 7864] Show Abstract ▼ Abstract: The leishmaniases, caused by Leishmania species of protozoan parasites, are neglected tropical diseases with 12-15 million cases worldwide. Current therapeutic approaches are limited by toxicity, resistance and cost. N-Myristoyltransferase (NMT), an enzyme ubiquitous and essential in all eukaryotes, has been validated via genetic and pharmacological methods as a promising antileishmanial target. Here we describe a comprehensive structure activity relationship study of a thienopyrimidine series previously identified in a high throughput screen against Leishmania NMT, across 68 compounds in enzyme- and cell-based assay formats. Using a chemical tagging target engagement biomarker assay we identify the first inhibitor in this series with on-target NMT activity in leishmania parasites. Furthermore, crystal structure analyses of 12 derivatives in complex with Leishmania major NMT revealed key factors important for future structure-guided optimization delivering IMP-105 (43), a compound with modest activity against L. donovani intracellular amastigotes and excellent selectivity (>660-fold) for Leishmania NMT over human NMTs.	Jun 2020
I04-Macromolecular Crystallography	Preclinical lead optimization of a 1,2,4-triazole based tankyrase inhibitor Jo Waaler , Ruben G. G. Leenders , Sven T. Sowa , Shoshy Alam Brinch , Max Lycke , Piotr Nieczypor , Sjoerd Aertssen , Sudarshan Murthy , Albert Galera-prat , Eddy Damen , Anita Wegert , Marc Nazaré , Lari Lehtiö , Stefan Krauss Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00208 Diamond Proposal Number(s): [19951] Show Abstract ▼ Abstract: Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC50 inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.	Jun 2020
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Receptor-interacting protein kinase 2 (RIPK2) and nucleotide-binding oligomerization domain (NOD) cell signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold Chalada Suebsuwong , Bing Dai , Daniel M. Pinkas , Anantha Lakshmi Duddupudi , Li Li , Joshua C. Bufton , Lisa Schlicher , Mads Gyrd-hansen , Ming Hu , Alex N. Bullock , Alexei Degterev , Gregory D. Cuny European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2020.112417 Diamond Proposal Number(s): [15433] Show Abstract ▼ Abstract: Receptor-interacting protein kinase 2 (RIPK2) is a key mediator of nucleotide-binding oligomerization domain (NOD) cell signaling that has been implicated in various chronic inflammatory conditions. A new class of RIPK2 kinase/NOD signaling inhibitors based on a 3,5-diphenyl-2-aminopyridine scaffold was developed. Several co-crystal structures of RIPK2•inhibitor complexes were analyzed to provide insights into inhibitor selectivity versus the structurally related activin receptor-like kinase 2 (ALK2) demonstrating that the inhibitor sits deeper in the hydrophobic binding pocket of RIPK2 perturbing the orientation of the DFG motif. In addition, the structure-activity relationship study revealed that in addition to anchoring to the hinge and DFG via the 2-aminopyridine and 3-phenylsulfonamide, respectively, appropriate occupancy of the region between the gatekeeper and the αC-helix provided by substituents in the 4- and 5-positions of the 3-phenylsulfonamide were necessary to achieve potent NOD cell signaling inhibition. For example, compound 18t (e.g. CSLP37) displayed potent biochemical RIPK2 kinase inhibition (IC50 = 16 ± 5 nM), >20-fold selectivity versus ALK2 and potent NOD cell signaling inhibition (IC50 = 26 ± 4 nM) in the HEKBlue assay. Finally, in vitro ADME and pharmacokinetic characterization of 18t further supports the prospects of the 3,5-diphenyl-2-aminopyridine scaffold for the generation of in vivo pharmacology probes of RIPK2 kinase and NOD cell signaling functions.	May 2020
I03-Macromolecular Crystallography	Targeting ALK2: An open science approach to developing therapeutics for the treatment of diffuse intrinsic pontine glioma Deeba Ensan , David Smil , Carlos A. Zepeda-velázquez , Dimitrios Panagopoulos , Jong Fu Wong , Eleanor P. Williams , Roslin Adamson , Alex N. Bullock , Taira Kiyota , Ahmed Aman , Owen G. Roberts , Aled M. Edwards , Jeff A. O’meara , Methvin B. Isaac , Rima Al-awar Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00395 Diamond Proposal Number(s): [19301] Show Abstract ▼ Abstract: Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a–c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.	May 2020
I04-Macromolecular Crystallography	Molecular basis for omapatrilat and sampatrilat binding to neprilysin – implications for dual inhibitor design with angiotensin converting enzyme Urvashi Sharma , Gyles E. Cozier , Edward D. Sturrock , K. Ravi Acharya Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00441 Diamond Proposal Number(s): [17212] Show Abstract ▼ Abstract: Neprilysin (NEP) and angiotensin-1 converting enzyme (ACE) are two key zinc-dependent metallopeptidases in the natriuretic peptide and kinin systems, and renin-angiotensin-aldosterone system, respectively. They play an important role in blood pressure regulation and reducing the risk of heart failure. Vasopeptidase inhibitors omapatrilat and sampatrilat possess dual activity against these enzymes by blocking the ACE-dependant conversion of angiotensin I to the potent vasoconstrictor angiotensin II while simultaneously halting the NEP-dependant degradation of vasodilator atrial natriuretic peptide. Here we report crystal structures of omapatrilat, sampatrilat and sampatrilat-ASP (a sampatrilat analogue) in complex with NEP at 1.75Å, 2.65Å and 2.6Å, respectively. A detailed analysis of these structures and the corresponding structures of ACE with these inhibitors has provided the molecular basis of dual inhibitor recognition involving the catalytic site in both enzymes. This new information will be very useful in the design of safer and more selective vasopeptidase inhibitors of NEP and ACE for effective treatment in hypertension and heart failure.	Apr 2020
I04-Macromolecular Crystallography	Optimisation of potent ATAD2 and CECR2 bromodomain inhibitors with an atypical binding mode Simon Lucas , Stephen J. Atkinson , Paul Bamborough , Heather A. Barnett , Chun-wa Chung , Laurie J. Gordon , Darren J. Mitchell , Alexander Phillipou , Rab K. Prinjha , Robert J. Sheppard , Nicholas C. O. Tomkinson , Robert J. Watson , Emmanuel H. Demont Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00021 Show Abstract ▼ Abstract: Most bromodomain inhibitors mimic the interactions of the natural acetylated lysine (KAc) histone substrate through key interactions with conserved asparagine and tyrosine residues within the binding pocket. Herein we report the optimisation of a series of phenyl sulfonamides which exhibit a novel mode of binding to non-Bromodomain and Extra Terminal Domain (non-BET) bromodomains through displacement of a normally conserved network of four water molecules. Starting from an initial hit molecule we report its divergent optimisation towards the ATPase family AAA domain containing 2 (ATAD2) and Cats Eye Syndrome Chromosome Region, Candidate 2 (CECR2) domains. This work concludes with the identification of (R)-55 (GSK232), a highly selective, cellularly penetrant CECR2 inhibitor with excellent physicochemical properties.	Apr 2020
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based design of Mycobacterium tuberculosis InhA inhibitors Mohamad Sabbah , Vitor Mendes , Robert G Vistal , David M. G. Dias , Monika Záhorszká , Katarína Mikušová , Jana Korduláková , Anthony G Coyne , Tom L. Blundell , Chris Abell Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00007 Diamond Proposal Number(s): [9537, 14043] Show Abstract ▼ Abstract: Tuberculosis (TB) remains a leading cause of mortality amongst infectious diseases worldwide. InhA, an enoyl ACP-reductase, has been the focus of numerous drug discovery efforts as this is the target of the first line pro-drug isoniazid. However, with resistance to this drug becoming more common the aim has been to find new clinical candidates that directly inhibit this enzyme and that do not require activation by the catalase peroxidase KatG, thus circumventing the majority of the resistance mechanisms. In this work, the screening and validation of a fragment library is described and development of the fragment hits using a fragment growing strategy was employed which led to the development InhA inhibitors with affinities of up to 250 nM.	Apr 2020

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