Search Results

You searched for all publications:

with publication states 'Published (Approved)'
published in journal 'Journal Of Medicinal Chemistry'

Search Again...

These results only include publications that have been reviewed and processed by Diamond Light Source. To also view papers that have not yet been processed click here.

You can use the folder icon under Actions to collate papers as required. You can then click on View Folder in the left-hand navigation to review and/or download your folder.

Exact matches
Related results

288 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	Discovery of an in vivo chemical probe for BCL6 inhibition by optimization of tricyclic quinolinones Alice C. Harnden , Owen A. Davis , Gary M. Box , Angela Hayes , Louise D. Johnson , Alan T. Henley , Alexis K. De Haven Brandon , Melanie Valenti , Kwai-Ming J. Cheung , Alfie Brennan , Rosemary Huckvale , Olivier A. Pierrat , Rachel Talbot , Michael D. Bright , Hafize Aysin Akpinar , Daniel S. J. Miller , Dalia Tarantino , Sharon Gowan , Selby De Klerk , Peter C. Mcandrew , Yann-Vai Le Bihan , Mirco Meniconi , Rosemary Burke , Vladimir Kirkin , Rob Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.3c00155 Diamond Proposal Number(s): [24828] Open Access Show Abstract ▼ Abstract: B-cell lymphoma 6 (BCL6) is a transcriptional repressor and oncogenic driver of diffuse large B-cell lymphoma (DLBCL). Here, we report the optimization of our previously reported tricyclic quinolinone series for the inhibition of BCL6. We sought to improve the cellular potency and in vivo exposure of the non-degrading isomer, CCT373567, of our recently published degrader, CCT373566. The major limitation of our inhibitors was their high topological polar surface areas (TPSA), leading to increased efflux ratios. Reducing the molecular weight allowed us to remove polarity and decrease TPSA without considerably reducing solubility. Careful optimization of these properties, as guided by pharmacokinetic studies, led to the discovery of CCT374705, a potent inhibitor of BCL6 with a good in vivo profile. Modest in vivo efficacy was achieved in a lymphoma xenograft mouse model after oral dosing.	Apr 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Tuning liver pyruvate kinase activity up or down with a new class of allosteric modulators Amalyn Nain-Perez , Oscar Nilsson , Aleksei Lulla , Liliana Håversen , Paul Brear , Sara Liljenberg , Marko Hyvonen , Jan Borén , Morten Grøtli European Journal Of Medicinal Chemistry 250 DOI: 10.1016/j.ejmech.2023.115177 Diamond Proposal Number(s): [18548, 25402] Open Access Show Abstract ▼ Abstract: The liver isoform of pyruvate kinase (PKL) has gained interest due to its potential capacity to regulate fatty acid synthesis involved in the progression of non-alcoholic fatty liver disease (NAFLD). Here we describe a novel series of PKL modulators that can either activate or inhibit the enzyme allosterically, from a cryptic site at the interface of two protomers in the tetrameric enzyme. Starting from urolithin D, we designed and synthesised 42 new compounds. The effect of these compounds on PKL enzymatic activity was assessed after incubation with cell lysates obtained from a liver cell line. Pronounced activation of PKL activity, up to 3.8-fold, was observed for several compounds at 10 μM, while other compounds were prominent PKL inhibitors reducing its activity to 81% at best. A structure-activity relationship identified linear-shaped sulfone-sulfonamides as activators and non-linear compounds as inhibitors. Crystal structures revealed the conformations of these modulators, which were used as a reference for designing new modulators.	Mar 2023
I04-Macromolecular Crystallography	New dual inhibitors of bacterial topoisomerases with broad-spectrum antibacterial activity and in vivo efficacy against vancomycin-intermediate Staphylococcus aureus Martina Durcik , Andrej Emanuel Cotman , Žan Toplak , Štefan Možina , Žiga Skok , Petra Eva Szili , Márton Czikkely , Elvin Maharramov , Thu Hien Vu , Maria Vittoria Piras , Nace Zidar , Janez Ilaš , Anamarija Zega , Jurij Trontelj , Luis A. Pardo , Diarmaid Hughes , Douglas Huseby , Tália Berruga-Fernández , Sha Cao , Ivailo Simoff , Richard Svensson , Sergiy V. Korol , Zhe Jin , Francisca Vicente , Maria C. Ramos , Julia E. A. Mundy , Anthony Maxwell , Clare E. M. Stevenson , David M. Lawson , Björn Glinghammar , Eva Sjöström , Martin Bohlin , Joanna Oreskär , Sofie Alvér , Guido V. Janssen , Geert Jan Sterk , Danijel Kikelj , Csaba Pal , Tihomir Tomašič , Lucija Peterlin Mašič Journal Of Medicinal Chemistry 1703 DOI: 10.1021/acs.jmedchem.2c01905 Diamond Proposal Number(s): [25108] Open Access Show Abstract ▼ Abstract: A new series of dual low nanomolar benzothiazole inhibitors of bacterial DNA gyrase and topoisomerase IV were developed. The resulting compounds show excellent broad-spectrum antibacterial activities against Gram-positive Enterococcus faecalis, Enterococcus faecium and multidrug resistant (MDR) Staphylococcus aureus strains [best compound minimal inhibitory concentrations (MICs): range, <0.03125–0.25 μg/mL] and against the Gram-negatives Acinetobacter baumannii and Klebsiella pneumoniae (best compound MICs: range, 1–4 μg/mL). Lead compound 7a was identified with favorable solubility and plasma protein binding, good metabolic stability, selectivity for bacterial topoisomerases, and no toxicity issues. The crystal structure of 7a in complex with Pseudomonas aeruginosa GyrB24 revealed its binding mode at the ATP-binding site. Expanded profiling of 7a and 7h showed potent antibacterial activity against over 100 MDR and non-MDR strains of A. baumannii and several other Gram-positive and Gram-negative strains. Ultimately, in vivo efficacy of 7a in a mouse model of vancomycin-intermediate S. aureus thigh infection was also demonstrated.	Mar 2023
	Antitarget, anti-SARS-CoV-2 leads, drugs, and the drug discovery - genetics alliance perspective Cecilia Pozzi , Anne Vanet , Valeria Francesconi , Lorenzo Tagliazucchi , Giusy Tassone , Alberto Venturelli , Francesca Spyrakis , Marco Mazzorana , Maria P. Costi , Michele Tonelli Journal Of Medicinal Chemistry 3 DOI: 10.1021/acs.jmedchem.2c01229 Open Access Show Abstract ▼ Abstract: The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying the target structural basis, its mutational progression, and the related biological significance to virus replication allows envisaging the development of better-targeted therapies in the context of COVID-19 epidemic and future coronavirus outbreaks. The identification of evolutionary patterns based solely on sequence information analysis for those targets can provide meaningful insights into the molecular basis of host–pathogen interactions and adaptation, leading to drug resistance phenomena. Herein, we will explore how the study of observed and predicted mutations may offer valuable suggestions for the application of the so-called “synthetic lethal” strategy to SARS-CoV-2 Main protease and Spike protein. The synergy between genetics evidence and drug discovery may prioritize the development of novel long-lasting antiviral agents.	Mar 2023
VMXm-Versatile Macromolecular Crystallography microfocus	Alkyne derivatives of SARS-CoV-2 main protease inhibitors including nirmatrelvir inhibit by reacting covalently with the nucleophilic cysteine Lennart Brewitz , Leo Dumjahn , Yilin Zhao , C. David Owen , Stephen M. Laidlaw , Tika R. Malla , Dung Nguyen , Petra Lukacik , Eidarus Salah , Adam D. Crawshaw , Anna J. Warren , Jose Trincao , Claire Strain-Damerell , Miles W. Carroll , Martin A. Walsh , Christopher J. Schofield Journal Of Medicinal Chemistry 374 DOI: 10.1021/acs.jmedchem.2c01627 Diamond Proposal Number(s): [27088] Open Access Show Abstract ▼ Abstract: Nirmatrelvir (PF-07321332) is a nitrile-bearing small-molecule inhibitor that, in combination with ritonavir, is used to treat infections by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nirmatrelvir interrupts the viral life cycle by inhibiting the SARS-CoV-2 main protease (Mpro), which is essential for processing viral polyproteins into functional nonstructural proteins. We report studies which reveal that derivatives of nirmatrelvir and other Mpro inhibitors with a nonactivated terminal alkyne group positioned similarly to the electrophilic nitrile of nirmatrelvir can efficiently inhibit isolated Mpro and SARS-CoV-2 replication in cells. Mass spectrometric and crystallographic evidence shows that the alkyne derivatives inhibit Mpro by apparent irreversible covalent reactions with the active site cysteine (Cys145), while the analogous nitriles react reversibly. The results highlight the potential for irreversible covalent inhibition of Mpro and other nucleophilic cysteine proteases by alkynes, which, in contrast to nitriles, can be functionalized at their terminal position to optimize inhibition and selectivity, as well as pharmacodynamic and pharmacokinetic properties.	Feb 2023
I04-Macromolecular Crystallography	Discovery of a potent and orally bioavailable zwitterionic series of selective estrogen receptor degrader-antagonists James S. Scott , Darren Stead , Bernard Barlaam , Jason Breed , Rodrigo J. Carbajo , Elisabetta Chiarparin , Natalie Cureton , Paul R. J. Davey , David I. Fisher , Eric T. Gangl , Tyler Grebe , Ryan D. Greenwood , Sudhir Hande , Holia Hatoum-Mokdad , Samantha J. Hughes , Thomas A. Hunt , Tony Johnson , Stefan L. Kavanagh , Teresa C. M. Klinowska , Carrie J. B. Larner , Mandy Lawson , Andrew S. Lister , David Longmire , Stacey Marden , Thomas M. Mcguire , Caroline Mcmillan , Lindsay Mcmurray , Christopher J. Morrow , J. Willem M. Nissink , Thomas A. Moss , Daniel H. O’donovan , Radoslaw Polanski , Stephen Stokes , Kumar Thakur , Dawn Trueman , Caroline Truman , Michael J. Tucker , Haixia Wang , Nicky Whalley , Dedong Wu , Ye Wu , Bin Yang , Wenzhan Yang Journal Of Medicinal Chemistry 61 DOI: 10.1021/acs.jmedchem.2c01964 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.	Feb 2023
I03-Macromolecular Crystallography	Design, synthesis and characterisation of a novel type II B-RAF paradox breaker inhibitor Rohit Arora , Joannes T. M. Linders , Samia Aci-Sèche , Thomas Verheyen , Erika Van Heerde , Dirk Brehmer , Apirat Chaikuad , Stefan Knapp , Pascal Bonnet European Journal Of Medicinal Chemistry 25 DOI: 10.1016/j.ejmech.2023.115231 Show Abstract ▼ Abstract: The mutation V600E in B-Raf leads to mitogen activated protein kinase (MAPK) pathway activation, uncontrolled cell proliferation, and tumorigenesis. ATP competitive type I B-Raf inhibitors, such as vemurafenib (1) and PLX4720 (4) efficiently block the MAPK pathways in B-Raf mutant cells, however these inhibitors induce conformational changes in the wild type B-Raf (wtB-Raf) kinase domain leading to heterodimerization with C-Raf, causing paradoxical hyperactivation of the MAPK pathway. This unwanted activation may be avoided by another class of inhibitors (type II) which bind the kinase in the DFG-out conformation, such as AZ628 (3) preventing heterodimerization. Here we present a new B-Raf kinase domain inhibitor, based on a phenyl(1H-pyrrolo [2,3-b]pyridin-3-yl)methanone template, that represents a hybrid between 4 and 3. This novel inhibitor borrows the hinge binding region from 4 and the back pocket binding moiety from 3. We determined its binding mode, performed activity/selectivity studies, and molecular dynamics simulations in order to study the conformational effects induced by this inhibitor on wt and V600E mutant B-Raf kinase. We discovered that the inhibitor was active and selective for B-Raf, binds in a DFG-out/αC-helix-in conformation, and did not induce the aforementioned paradoxical hyperactivation in the MAPK pathway. We propose that this merging approach can be used to design a novel class of B-Raf inhibitors for translational studies.	Feb 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Discovery and hit-to-lead optimization of benzothiazole scaffold-based DNA gyrase inhibitors with potent activity against Acinetobacter baumannii and Pseudomonas aeruginosa Andrej Emanuel Cotman , Martina Durcik , Davide Benedetto Tiz , Federica Fulgheri , Daniela Secci , Maša Sterle , Štefan Možina , Žiga Skok , Nace Zidar , Anamarija Zega , Janez Ilaš , Lucija Peterlin Mašič , Tihomir Tomašič , Diarmaid Hughes , Douglas L. Huseby , Sha Cao , Linnéa Garoff , Talía Berruga Fernández , Paraskevi Giachou , Lisa Crone , Ivailo Simoff , Richard Svensson , Bryndis Birnir , Sergiy V. Korol , Zhe Jin , Francisca Vicente , Maria C. Ramos , Mercedes De La Cruz , Björn Glinghammar , Lena Lenhammar , Sara R. Henderson , Julia E. A. Mundy , Anthony Maxwell , Claren E. M. Stevenson , David M. Lawson , Guido V. Janssen , Geert Jan Sterk , Danijel Kikelj Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.2c01597 Diamond Proposal Number(s): [18565, 25108] Open Access Show Abstract ▼ Abstract: We have developed compounds with a promising activity against Acinetobacter baumannii and Pseudomonas aeruginosa, which are both on the WHO priority list of antibiotic-resistant bacteria. Starting from DNA gyrase inhibitor 1, we identified compound 27, featuring a 10-fold improved aqueous solubility, a 10-fold improved inhibition of topoisomerase IV from A. baumannii and P. aeruginosa, a 10-fold decreased inhibition of human topoisomerase IIα, and no cross-resistance to novobiocin. Cocrystal structures of 1 in complex with Escherichia coli GyrB24 and (S)-27 in complex with A. baumannii GyrB23 and P. aeruginosa GyrB24 revealed their binding to the ATP-binding pocket of the GyrB subunit. In further optimization steps, solubility, plasma free fraction, and other ADME properties of 27 were improved by fine-tuning of lipophilicity. In particular, analogs of 27 with retained anti-Gram-negative activity and improved plasma free fraction were identified. The series was found to be nongenotoxic, nonmutagenic, devoid of mitochondrial toxicity, and possessed no ion channel liabilities.	Jan 2023
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	[1,2,4]Triazolo[3,4-b]benzothiazole scaffold as versatile nicotinamide mimic allowing nanomolar inhibition of different PARP enzymes Sudarshan Murthy , Maria Giulia Nizi , Mirko M. Maksimainen , Serena Massari , Juho Alaviuhkola , Barbara E. Lippok , Chiara Vagaggini , Sven T. Sowa , Albert Galera-Prat , Yashwanth Ashok , Harikanth Venkannagari , Renata Prunskaite-Hyyryläinen , Elena Dreassi , Bernhard Lüscher , Patricia Korn , Oriana Tabarrini , Lari Lehtio Journal Of Medicinal Chemistry 40 DOI: 10.1021/acs.jmedchem.2c01460 Diamond Proposal Number(s): [23346, 26794, 19951] Open Access Show Abstract ▼ Abstract: We report [1,2,4]triazolo[3,4-b]benzothiazole (TBT) as a new inhibitor scaffold, which competes with nicotinamide in the binding pocket of human poly- and mono-ADP-ribosylating enzymes. The binding mode was studied through analogues and cocrystal structures with TNKS2, PARP2, PARP14, and PARP15. Based on the substitution pattern, we were able to identify 3-amino derivatives 21 (OUL243) and 27 (OUL232) as inhibitors of mono-ARTs PARP7, PARP10, PARP11, PARP12, PARP14, and PARP15 at nM potencies, with 27 being the most potent PARP10 inhibitor described to date (IC50 of 7.8 nM) and the first PARP12 inhibitor ever reported. On the contrary, hydroxy derivative 16 (OUL245) inhibits poly-ARTs with a selectivity toward PARP2. The scaffold does not possess inherent cell toxicity, and the inhibitors can enter cells and engage with the target protein. This, together with favorable ADME properties, demonstrates the potential of TBT scaffold for future drug development efforts toward selective inhibitors against specific enzymes.	Jan 2023
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Designed switch from covalent to non-covalent inhibitors of carboxylesterase Notum activity Benjamin N. Atkinson , Nicky J. Willis , Yuguang Zhao , Chandni Patel , Sarah Frew , Kathryn Costelloe , Lorenza Magno , Fredrik Svensson , E. Yvonne Jones , Paul V. Fish European Journal Of Medicinal Chemistry 519 DOI: 10.1016/j.ejmech.2023.115132 Diamond Proposal Number(s): [28534] Open Access Show Abstract ▼ Abstract: N-Acyl indolines 4 are potent, non-covalent Notum inhibitors developed from a covalent virtual screening hit 2a. The lead compounds were simple to synthesise, achieved excellent potency in a biochemical Notum-OPTS assay and restored Wnt signalling in a cell-based TCF/LEF reporter assay. Multiple high resolution X-ray structures established a common binding mode of these inhibitors with the indoline bound centred in the palmiteolate pocket with key interactions being aromatic stacking and a water mediated hydrogen bond to the oxyanion hole. These N-acyl indolines 4 will be useful tools for use in vitro studies to investigate the role of Notum in disease models, especially when paired with a structurally related covalent inhibitor (e.g. 4w and 2a). Overall, this study highlights the designed switch from covalent to non-covalent Notum inhibitors and so illustrates a complementary approach for hit generation and target inhibition.	Jan 2023

Publications Database

Search Results

You searched for all publications:

Search Again...

Subject Areas (check all that apply) select all

Instruments used to collect data (check all that apply) select all

Collaborations involved (check all that apply) select all

Diamond Offline Facilities used

Relevant Technical Areas (check all that apply) select all

Menu for Anonymous User