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263 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
I03-Macromolecular Crystallography	Potent 2,3-dihydrophthalazine-1,4-dione derivatives as dual inhibitors for mono-ADP-ribosyltransferases PARP10 and PARP15 Maria Giulia Nizi , Mirko M. Maksimainen , Sudarshan Murthy , Serena Massari , Juho Alaviuhkola , Barbara E. Lippok , Sven T. Sowa , Albert Galera-Prat , Renata Prunskaite-Hyyryläinen , Bernhard Lüscher , Patricia Korn , Lari Lehtio , Oriana Tabarrini European Journal Of Medicinal Chemistry 237 DOI: 10.1016/j.ejmech.2022.114362 Diamond Proposal Number(s): [19951] Show Abstract ▼ Abstract: While human poly-ADP-ribose chain generating poly-ARTs, PARP1 and 2 and TNKS1 and 2, have been widely characterized, less is known on the pathophysiological roles of the mono-ADP-ribosylating mono-ARTs, partly due to the lack of selective inhibitors. In this context, we have focused on the development of inhibitors for the mono-ART PARP10, whose overexpression is known to induce cell death. Starting from OUL35 (1) and its 4-(benzyloxy)benzamidic derivative (2) we herein report the design and synthesis of new analogues from which the cyclobutyl derivative 3c rescued cells most efficiently from PARP10 induced apoptosis. Most importantly, we also identified 2,3-dihydrophthalazine-1,4-dione as a new suitable nicotinamide mimicking PARP10 inhibitor scaffold. When it was functionalized with cycloalkyl (8a-c), o-fluorophenyl (8h), and thiophene (8l) rings, IC50 values in the 130–160 nM range were obtained, making them the most potent PARP10 inhibitors reported to date. These compounds also inhibited PARP15 with low micromolar IC50s, but none of the other tested poly- and mono-ARTs, thus emerging as dual mono-ART inhibitors. Compounds 8a, 8h and 8l were also able to enter cells and rescue cells from apoptosis. Our work sheds more light on inhibitor development against mono-ARTs and identifies chemical probes to study the cellular roles of PARP10 and PARP15.	Jul 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Multitarget, selective compound design yields potent inhibitors of a kinetoplastid pteridine reductase 1 Ina Pöhner , Antonio Quotadamo , Joanna Panecka-Hofman , Rosaria Luciani , Matteo Santucci , Pasquale Linciano , Giacomo Landi , Flavio Di Pisa , Lucia Dello Iacono , Cecilia Pozzi , Stefano Mangani , Sheraz Gul , Gesa Witt , Bernhard Ellinger , Maria Kuzikov , Nuno Santarem , Anabela Cordeiro-Da-Silva , Maria P. Costi , Alberto Venturelli , Rebecca C. Wade Journal Of Medicinal Chemistry 51 DOI: 10.1021/acs.jmedchem.2c00232 Open Access Show Abstract ▼ Abstract: The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present a systematic, multidisciplinary approach to the development of selective antiparasitic compounds. Computational fragment-based design of novel pteridine derivatives along with iterations of crystallographic structure determination allowed for the derivation of a structure–activity relationship for multitarget inhibition. The approach yielded compounds showing apparent picomolar inhibition of T. brucei pteridine reductase 1 (PTR1), nanomolar inhibition of L. major PTR1, and selective submicromolar inhibition of parasite dihydrofolate reductase (DHFR) versus human DHFR. Moreover, by combining design for polypharmacology with a property-based on-parasite optimization, we found three compounds that exhibited micromolar EC50 values against T. brucei brucei while retaining their target inhibition. Our results provide a basis for the further development of pteridine-based compounds, and we expect our multitarget approach to be generally applicable to the design and optimization of anti-infective agents.	Jun 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Optimizing shape complementarity enables the discovery of potent tricyclic BCL6 inhibitors Owen A. Davis , Kwai-Ming J. Cheung , Alfie Brennan , Matthew G. Lloyd , Matthew J. Rodrigues , Olivier A. Pierrat , Gavin W. Collie , Yann-Vai Le Bihan , Rosemary Huckvale , Alice C. Harnden , Ana Varela , Michael D. Bright , Paul Eve , Angela Hayes , Alan T. Henley , Michael D. Carter , P. Craig Mcandrew , Rachel Talbot , Rosemary Burke , Rob Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Mirco Meniconi , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c02174 Open Access Show Abstract ▼ Abstract: To identify new chemical series with enhanced binding affinity to the BTB domain of B-cell lymphoma 6 protein, we targeted a subpocket adjacent to Val18. With no opportunities for strong polar interactions, we focused on attaining close shape complementarity by ring fusion onto our quinolinone lead series. Following exploration of different sized rings, we identified a conformationally restricted core which optimally filled the available space, leading to potent BCL6 inhibitors. Through X-ray structure-guided design, combined with efficient synthetic chemistry to make the resulting novel core structures, a >300-fold improvement in activity was obtained by the addition of seven heavy atoms.	Jun 2022
I03-Macromolecular Crystallography	Improved binding affinity and pharmacokinetics enable sustained degradation of BCL6 in vivo Rosemary Huckvale , Alice C. Harnden , Kwai-Ming J. Cheung , Olivier A. Pierrat , Rachel Talbot , Gary M. Box , Alan T. Henley , Alexis K. De Haven Brandon , Albert E. Hallsworth , Michael D. Bright , Hafize Aysin Akpinar , Daniel S. J. Miller , Dalia Tarantino , Sharon Gowan , Angela Hayes , Emma A. Gunnell , Alfie Brennan , Owen A. Davis , Louise D. Johnson , Selby De Klerk , Craig Mcandrew , Yann-Vai Le Bihan , Mirco Meniconi , Rosemary Burke , Vladimir Kirkin , Rob L. M. Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c02175 Open Access Show Abstract ▼ Abstract: The transcriptional repressor BCL6 is an oncogenic driver found to be deregulated in lymphoid malignancies. Herein, we report the optimization of our previously reported benzimidazolone molecular glue-type degrader CCT369260 to CCT373566, a highly potent probe suitable for sustained depletion of BCL6 in vivo. We observed a sharp degradation SAR, where subtle structural changes conveyed the ability to induce degradation of BCL6. CCT373566 showed modest in vivo efficacy in a lymphoma xenograft mouse model following oral dosing.	Jun 2022
I03-Macromolecular Crystallography	Phenyl Bis-sulfonamide Keap1-Nrf2 protein–protein interaction inhibitors with an alternative binding mode Nikolaos Georgakopoulos , Sandeep Talapatra , Dina Dikovskaya , Sharadha Dayalan Naidu , Maureen Higgins , Jemma Gatliff , Aysel Ayhan , Roxani Nikoloudaki , Marjolein Schaap , Klara Valko , Farideh Javid , Albena T. Dinkova-Kostova , Frank Kozielski , Geoffrey Wells Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.2c00457 Diamond Proposal Number(s): [12305] Open Access Show Abstract ▼ Abstract: Inhibitors of Kelch-like ECH-associated protein 1 (Keap1) increase the activity of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) by stalling its ubiquitination and degradation. This enhances the expression of genes encoding proteins involved in drug detoxification, redox homeostasis, and mitochondrial function. Nrf2 activation offers a potential therapeutic approach for conditions including Alzheimer’s and Parkinson’s diseases, vascular inflammation, and chronic obstructive airway disease. Non-electrophilic Keap1-Nrf2 protein–protein interaction (PPI) inhibitors may have improved toxicity profiles and different pharmacological properties to cysteine-reactive electrophilic inhibitors. Here, we describe and characterize a series of phenyl bis-sulfonamide PPI inhibitors that bind to Keap1 at submicromolar concentrations. Structural studies reveal that the compounds bind to Keap1 in a distinct “peptidomimetic” conformation that resembles the Keap1-Nrf2 ETGE peptide complex. This is different to other small molecule Keap1-Nrf2 PPI inhibitors, including bicyclic aryl bis-sulfonamides, offering a starting point for new design approaches to Keap1 inhibitors.	May 2022
I04-Macromolecular Crystallography	Discovery of AZD4625, a covalent allosteric inhibitor of the mutant GTPase KRASG12C Jason G. Kettle , Sharan K. Bagal , Sue Bickerton , Michael S. Bodnarchuk , Scott Boyd , Jason Breed , Rodrigo J. Carbajo , Doyle J. Cassar , Atanu Chakraborty , Sabina Cosulich , Iain Cumming , Michael Davies , Nichola L. Davies , Andrew Eatherton , Laura Evans , Lyman Feron , Shaun Fillery , Emma S. Gleave , Frederick W. Goldberg , Lyndsey Hanson , Stephanie Harlfinger , Martin Howard , Rachel Howells , Anne Jackson , Paul Kemmitt , Gillian Lamont , Scott Lamont , Hilary J. Lewis , Libin Liu , Michael J. Niedbala , Christopher Phillips , Radek Polanski , Piotr Raubo , Graeme Robb , David M. Robinson , Sarah Ross , Matthew G. Sanders , Michael Tonge , Rebecca Whiteley , Stephen Wilkinson , Junsheng Yang , Wenman Zhang Journal Of Medicinal Chemistry 65, 6940 - 6952 DOI: 10.1021/acs.jmedchem.2c00369 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.	May 2022
I04-1-Macromolecular Crystallography (fixed wavelength)	Design of a potent, selective, and brain-penetrant inhibitor of Wnt-deactivating enzyme notum by optimization of a crystallographic fragment hit Nicky J. Willis , William Mahy , James Sipthorp , Yuguang Zhao , Hannah L. Woodward , Benjamin N. Atkinson , Elliott D. Bayle , Fredrik Svensson , Sarah Frew , Fiona Jeganathan , Amy Monaghan , Stefano Benvegnù , Sarah Jolly , Luca Vecchia , Reinis R. Ruza , Svend Kjær , Steven Howell , Ambrosius P. Snijders , Magda Bictash , Patricia C. Salinas , Jean-Paul Vincent , E. Yvonne Jones , Paul Whiting , Paul V. Fish Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.2c00162 Diamond Proposal Number(s): [16814, 19446] Open Access Show Abstract ▼ Abstract: Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer’s disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.	May 2022
I03-Macromolecular Crystallography	Penicillin derivatives inhibit the SARS-COV-2 main protease by reaction with its nucleophilic cysteine Tika R. Malla , Lennart Brewitz , Dorian-Gabriel Muntean , Hiba Aslam , C. David Owen , Eidarus Salah , Anthony Tumber , Petra Lukacik , Claire Strain-Damerell , Halina Mikolajek , Martin Walsh , Christopher J. Schofield Journal Of Medicinal Chemistry 49 DOI: 10.1021/acs.jmedchem.1c02214 Diamond Proposal Number(s): [27088] Open Access Show Abstract ▼ Abstract: The SARS-CoV-2 main protease (Mpro) is a medicinal chemistry target for COVID-19 treatment. Given the clinical efficacy of β-lactams as inhibitors of bacterial nucleophilic enzymes, they are of interest as inhibitors of viral nucleophilic serine and cysteine proteases. We describe the synthesis of penicillin derivatives which are potent Mpro inhibitors and investigate their mechanism of inhibition using mass spectrometric and crystallographic analyses. The results suggest that β-lactams have considerable potential as Mpro inhibitors via a mechanism involving reaction with the nucleophilic cysteine to form a stable acyl–enzyme complex as shown by crystallographic analysis. The results highlight the potential for inhibition of viral proteases employing nucleophilic catalysis by β-lactams and related acylating agents.	May 2022
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Parallel optimization of potency and pharmacokinetics leading to the discovery of a pyrrole carboxamide ERK5 kinase domain inhibitor Duncan C. Miller , Tristan Reuillon , Lauren Molyneux , Timothy Blackburn , Simon J. Cook , Noel Edwards , Jane A. Endicott , Bernard T. Golding , Roger J. Griffin , Ian Hardcastle , Suzannah J. Harnor , Amy Heptinstall , Pamela Lochhead , Mathew P. Martin , Nick C. Martin , Stephanie Myers , David R. Newell , Richard A. Noble , Nicole Phillips , Laurent Rigoreau , Huw Thomas , Julie A. Tucker , Lan-Zhen Wang , Michael J. Waring , Ai-Ching Wong , Stephen R. Wedge , Martin E. M. Noble , Celine Cano Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01756 Diamond Proposal Number(s): [9948, 13587] Show Abstract ▼ Abstract: The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and in vitro pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.	Apr 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Anthraquinone derivatives as ADP-competitive inhibitors of liver pyruvate kinase Amalyn Nain-Perez , Anders Foller Füchtbauer , Liliana Håversen , Aleksei Lulla , Chunxia Gao , Josipa Matic , Leticia Monjas , Alexandra Rodríguez , Paul Brear , Woonghee Kim , Marko Hyvonen , Jan Borén , Adil Mardinoglu , Mathias Uhlen , Morten Grøtli European Journal Of Medicinal Chemistry 41 DOI: 10.1016/j.ejmech.2022.114270 Diamond Proposal Number(s): [25402] Show Abstract ▼ Abstract: Liver pyruvate kinase (PKL) is a major regulator of metabolic flux and ATP production during liver cell glycolysis and is considered a potential drug target for the treatment of non-alcoholic fatty liver disease (NAFLD). In this study, we report the first ADP-competitive PKL inhibitors and identify several starting points for the further optimization of these inhibitors. Modeling and structural biology guided the optimization of a PKL-specific anthraquinone-based compound. A structure–activity relationship study of 47 novel synthetic derivatives revealed PKL inhibitors with half-maximal inhibitory concentration (IC50) values in the 200 nM range. Despite the difficulty involved in studying a binding site as exposed as the ADP site, these derivatives feature expanded structural diversity and chemical spaces that may be used to improve their inhibitory activities against PKL. The obtained results expand the knowledge of the structural requirements for interactions with the ADP-binding site of PKL.	Mar 2022

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