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

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of a selective c-MET inhibitor with a novel binding mode Gavin W. Collie , Louise Barlind , Sana Bazzaz , Ulf Börjesson , Ian L. Dale , Jeremy S. Disch , Sevan Habeshian , Rachael Jetson , Puneet Khurana , Andrew Madin , Iacovos N. Michaelides , Ling Peng , Arjan Snijder , Christopher J. Stubbs Bioorganic & Medicinal Chemistry Letters 12 DOI: 10.1016/j.bmcl.2022.128948 Diamond Proposal Number(s): [17180, 20015] Open Access Show Abstract ▼ Abstract: The c-MET receptor tyrosine kinase has received considerable attention as a cancer drug target yet there remains a need for inhibitors which are selective for c-MET and able to target emerging drug-resistant mutants. We report here the discovery, by screening a DNA-encoded chemical library, of a highly selective c-MET inhibitor which was shown by X-ray crystallography to bind to the kinase in an unprecedented manner. These results represent a novel mode of inhibiting c-MET with a small molecule and may provide a route to targeting drug-resistant forms of the kinase whilst avoiding potential toxicity issues associated with broad kinome inhibition.	Aug 2022
I03-Macromolecular Crystallography	Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs Mirko M. Maksimainen , Sudarshan Murthy , Sven T. Sowa , Albert Galera-Prat , Elena Rolina , Juha P. Heiskanen , Lari Lehtio Bioorganic & Medicinal Chemistry 52 DOI: 10.1016/j.bmc.2021.116511 Diamond Proposal Number(s): [19951] Open Access Show Abstract ▼ Abstract: The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10–20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.	Dec 2021
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
I04-Macromolecular Crystallography	Next generation Glucose-1-phosphate thymidylyltransferase (RmlA) inhibitors: An extended SAR study to direct future design Ganyuan Xiao , Magnus S. Alphey , Fanny Tran , Lisa Pirrie , Pierre Milbeo , Yi Zhou , Jasmine K. Bickel , Oxana Kempf , Karl Kempf , James H. Naismith , Nicholas J. Westwood Bioorganic & Medicinal Chemistry 12 DOI: 10.1016/j.bmc.2021.116477 Show Abstract ▼ Abstract: The monosaccharide L-Rhamnose is an important component of bacterial cell walls. The first step in the L-rhamnose biosynthetic pathway is catalysed by glucose-1-phosphate thymidylyltransferase (RmlA), which condenses glucose-1-phosphate (Glu-1-P) with deoxythymidine triphosphate (dTTP) to yield dTDP-D-glucose. In addition to the active site where catalysis of this reaction occurs, RmlA has an allosteric site that is important for its function. Building on previous reports, SAR studies have explored further the allosteric site, leading to the identification of very potent P. aeruginosa RmlA inhibitors. Modification at the C6-NH2 of the inhibitor’s pyrimidinedione core structure was tolerated. X-ray crystallographic analysis of the complexes of P.aeruginosa RmlA with the novel analogues revealed that C6-aminoalkyl substituents can be used to position a modifiable amine just outside the allosteric pocket. This opens up the possibility of linking a siderophore to this class of inhibitor with the goal of enhancing bacterial cell wall permeability.	Oct 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
I03-Macromolecular Crystallography	Improving metabolic stability and removing aldehyde oxidase liability in a 5-azaquinazoline series of IRAK4 inhibitors Sébastien L. Degorce , Anna Aagaard , Rana Anjum , Iain A. Cumming , Coura R. Diène , Charlene Fallan , Tony Johnson , Karl-Johan Leuchowius , Alexandra L. Orton , Stuart Pearson , Graeme R. Robb , Alan Rosen , Graeme B. Scarfe , James S. Scott , James M. Smith , Oliver R. Steward , Ina Terstiege , Michael J. Tucker , Paul Turner , Stephen D. Wilkinson , Gail L. Wrigley , Yafeng Xue Bioorganic & Medicinal Chemistry 28 DOI: 10.1016/j.bmc.2020.115815 Show Abstract ▼ Abstract: In this article, we report our efforts towards improving in vitro human clearance in a series of 5-azaquinazolines through a series of C4 truncations and C2 expansions. Extensive DMPK studies enabled us to tackle high Aldehyde Oxidase (AO) metabolism and unexpected discrepancies in human hepatocyte and liver microsomal intrinsic clearance. Our efforts culminated with the discovery of 5-azaquinazoline 35, which also displayed exquisite selectivity for IRAK4, and showed synergistic in vitro activity against MyD88/CD79 double mutant ABC-DLBCL in combination with the covalent BTK inhibitor acalabrutinib.	Dec 2020
I04-Macromolecular Crystallography I23-Long wavelength MX	Crystal structure of Leishmania mexicana cysteine protease B in complex with a highly potent azadipeptide nitrile inhibitor Jean F. R. Ribeiro , Lorenzo Cianni , Chan Li , Thomas G. Warwick , Daniela De Vita , Fabiana Rosini , Fernanda Dos Reis Rocho , Felipe G. P. Martins , Peter W. Kenny , Jeronimo Lameira , Andrei Leitão , Jonas Emsley , Carlos A. Montanari Bioorganic & Medicinal Chemistry DOI: 10.1016/j.bmc.2020.115743 Diamond Proposal Number(s): [19880] Show Abstract ▼ Abstract: Leishmania mexicana is an obligate intracellular protozoan parasite that causes the cutaneous form of leishmaniasis affecting South America and Mexico. The cysteine protease LmCPB is essential for the virulence of the parasite and therefore, it is an appealing target for antiparasitic therapy. A library of nitrile-based cysteine protease inhibitors was screened against LmCPB to develop a treatment of cutaneous leishmaniasis. Several compounds are sufficiently high-affinity LmCPB inhibitors to serve both as starting points for drug discovery projects and as probes for target validation. A 1.4 Å X-ray crystal structure, the first to be reported for LmCPB, was determined for the complex of this enzyme covalently bound to an azadipeptide nitrile ligand. Mapping the structure-activity relationships for LmCPB inhibition revealed superadditive effects for two pairs of structural transformations. Therefore, this work advances our understanding of azadipeptidyl and dipeptidyl nitrile structure-activity relationships for LmCPB structure-based inhibitor design. We also tested the same series of inhibitors on related cysteine proteases cathepsin L and Trypanosoma cruzi cruzain. The modulation of these mammalian and protozoan proteases represents a new framework for targeting papain-like cysteine proteases.	Sep 2020
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

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