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375 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	Nanoscale direct-to-biology optimization and structural insights into selective S. aureus TrmD inhibitors Ariane F. Hübner , Annabelle C. Weldert , Tessa Marciniak , Florian Hof , Vivien S. Beck , Samuel Carien , Sophie N. Mulartschyk , Eva Wolf , Wilma Ziebuhr , Fabian Barthels Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c02323 Diamond Proposal Number(s): [36097] Open Access Show Abstract ▼ Abstract: The tRNA m1G37 methyltransferase (TrmD) is considered essential in various bacteria, including Staphylococcus aureus, a pathogen responsible for a wide range of diseases. Here, we have performed a high-throughput nanomole-scale synthesis campaign (nanoSAR) by late-stage copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC)-functionalizing a library of structurally diverse azides (N = 320) to a pyrrolopyrimidone alkyne. We have identified selective S. aureus TrmD inhibitors with inhibitory activity in the nanomolar to low micromolar range using a direct-to-biology assay read-out. A carbamate-masked guanidine intermediate of the lead structure selectively inhibited S. aureus growth at low micromolar concentrations in cell-based assays, while Gram-negative bacteria and an off-target panel of methyltransferases were not affected. Subsequent cocrystallization resulted in a crystal structure of S. aureus TrmD bound to an inhibitor, providing detailed insights into its binding mode and enabling future structure-guided optimization.	Dec 2025
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fluorescent binding assay for allosteric ligands of liver pyruvate kinase Oscar Nilsson , Agnieszka Bogucka , István Köteles , Liliana Håversen , Sara Liljenberg , Mikael Rutberg , Marko Hyvonen , Morten Grøtli European Journal Of Medicinal Chemistry 298 DOI: 10.1016/j.ejmech.2025.117989 Diamond Proposal Number(s): [25402, 33658] Open Access Show Abstract ▼ Abstract: Environment-sensitive fluorescent probes are indispensable tools for studying biological systems and advancing drug discovery. This study reports the development of 4-sulfamoyl-7-aminobenzoxadiazole (SBD)-based fluorescent probes for the allosteric site of the liver isoform of pyruvate kinase (PKL). By integrating SBD moieties into known activator scaffolds, such as mitapivat and diarylsulfonamide (DASA) ligands, probes for indicator displacement assays were designed to quantify ligand interactions in the allosteric site. Compound 4a displayed dose-dependent fluorescence enhancement in response to PKL binding and was used in a competitive binding assay with unlabelled ligands: mitapivat, TEPP-46, DASA-58 and reported activator 21. Structure–activity relationship (SAR) analysis revealed key structural features influencing activity and fluorescence sensitivity. The probes report selectively on the allosteric site ligands as the binding was not affected by natural ligands, such as ADP, fructose-1,6-bisphosphate (FBP), phosphoenolpyruvate (PEP), and phenylalanine. These findings provide a practical framework for detecting allosteric ligand engagement in PKL and expand the repertoire of molecular tools for advancing PKL-targeted therapies.	Nov 2025
I02-Macromolecular Crystallography	Design, synthesis, and biological evaluation of the novel neutrophil elastase inhibitor CHF-6333 for the inhaled treatment of bronchiectasis Elisabetta Armani , Andrea Rizzi , Daniela Miglietta , Irene Bassanetti , Francesco Amadei , Giandomenico Brogin , Carmelida Capaldi , Fabio Rancati , Chiara Carnini , Sergio Xanxo Fernandez , Maurizio Civelli , Paola Puccini , Marta Bellini , Andrew Jennings , Robert A. Heald , Lilian Alcaraz , Jonathan M. Sutton , Harry Finch , Mary Fitzgerald , Craig Fox , Gino Villetti Journal Of Medicinal Chemistry 207 DOI: 10.1021/acs.jmedchem.5c02638 Show Abstract ▼ Abstract: The inhibitors of neutrophil elastase (NE) have long attracted interest for the treatment of respiratory diseases. We report the breakthrough of a new potent, selective NE inhibitor with a 24 h duration of action: CHF-6333, is currently undergoing clinical studies for the inhaled treatment of bronchiectasis (BE). The story of the discovery project to identify novel small molecules that inhibit extracellular elastase in the lung with prolonged activity is described. Medicinal chemistry investigation, supported by docking studies, led to N-quaternary compounds with an in vitro profile suitable for inhalatory administration. Compound 15 emerged from in vivo pharmacokinetic and pharmacodynamic studies, also showing safety and no off-target effects in vitro. Salt screening of different counterions, in conjunction with in vivo local irritancy testing, aided in the selection of compound 15-xinafoate (CHF-6333). Efficacy in a lung injury model and no findings in non-GLP toxicity studies promoted CHF-6333 as a clinical candidate.	Nov 2025
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Exploiting the cryptic αd pocket of casein kinase 2α (CK2α) to deliver highly potent and selective Type 1 inhibitors Paul A. Glossop , Paul Brear , Susanne Wright , Neil Flanagan , Melanie S. Glossop , Charlotte A. L. Lane , Richard P. Butt , David R. Spring , Marko Hyvonen , Darren Cawkill Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c01807 Diamond Proposal Number(s): [14043, 18548, 25402] Open Access Show Abstract ▼ Abstract: Casein kinase 2α (CK2α) is an oncology drug target that acts as a positive regulator of many tumorigenic signaling pathways. We previously reported that CK2α has a unique cryptic binding site, the αD pocket, that offers the potential for inhibitors with improved kinase selectivity. The prototype bivalent molecule CAM4066 (6) confirmed that improved selectivity could be achieved while binding in both the ATP-binding site and the αD pocket. A drug discovery project to develop a new series of bivalent CK2α inhibitors with increased cell potency and selectivity identified 61f (APL-5125), a highly potent, ATP-competitive CK2α inhibitor with exquisite kinase selectivity and cellular potency. Compound 61f demonstrates in vivo inhibition of p-AKT S129 in tumors (HCT116) following once-daily oral administration and shows a clear PK–PD relationship with unbound drug exposure. 61f has a superior preclinical profile to existing CK2α inhibitors and is currently under evaluation in patients with advanced solid tumors.	Oct 2025
I04-Macromolecular Crystallography	Accelerated in silico discovery of SGR-1505: A potent MALT1 allosteric inhibitor for the treatment of mature B-cell malignancies Zhe Nie , Michael Trzoss , Andrew T. Placzek , Lynnie Trzoss , Goran Krilov , Shulu Feng , Morgan Lawrenz , Min Ye , Netonia Marshall , Karen H. Dingley , Robert D. Pelletier , W. George Lai , Jeffrey A. Bell , Haifeng Tang , Paul Devine , Zhijie Liu , Peter Skrdla , Roman Shimanovich , Matt Liu , Renchao Wang , Xiaoming Xu , Robert Abel , Karen Akinsanya , Wu Yin Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c01494 Show Abstract ▼ Abstract: MALT1 is a key component of the CARD11-BCL10-MALT1 (CBM) complex downstream from BTK on the B-cell receptor signaling pathway. It is a key mediator of NF-κB signaling and considered a potential therapeutic target for several subtypes of non-Hodgkin’s B-cell lymphomas. By applying advanced physics-based modeling techniques, including combining free energy calculations with machine learning methods and a chemistry-aware compound enumeration workflow, extensive sets of de novo design ideas were explored to quickly identify a novel hit series. Multiparameter optimization allowed efficient prioritization of molecules with good potency and drug-like properties during lead optimization, which led to the discovery of a highly potent MALT1 inhibitor, SGR-1505, with a well-balanced property profile. It demonstrated strong antitumor activity alone and in combination with BTK inhibitor in multiple in vivo B-cell lymphoma xenograft models and progressed to a phase 1 clinical trial in patients with mature B-cell neoplasms.	Oct 2025
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Design of bicyclic peptide tandems mimicking the homodimeric GDF15 protein to inhibit GDF15-GFRaL-RET complex cell signaling Anaïs F. M. Noisier , Jenny Sandmark , Fredrik Edfeldt , Anna Backmark , Johan Broddefalk , Joanna Wandzik , Ulrik Jurva , Margareta Ek , Carina A. Johansson , Louise Barlind , Jenny Gunnarsson , Janna M. Bigalke , Yafeng Xue , Andrey I. Frolov , Cecilia Kankkonen , Robert G. Roth , Maria Fritsch , Sophie Watcham , Katerine Van Rietschoten , Gemma E. Mudd , Helen Harrison , Liuhong Chen , Michael J. Skynner , David J. Craik , Sunay V. Chankeshwara , Malin Lemurell Journal Of Medicinal Chemistry 647 DOI: 10.1021/acs.jmedchem.5c01378 Show Abstract ▼ Abstract: The GDF15–GFRaL–RET signaling complex is involved in a broad range of disease states, with agonistic action of GDF15 affecting metabolism and body weight control, while inhibition is indicated in cancer and wasting disorders like cachexia. Here, we describe the discovery of the peptide inhibitors of the GDF15–GFRaL protein–protein interaction to prevent RET-induced signaling using both a structure-guided design and a phage display approach. Phage display provided bicyclic peptide hits with high affinity for GFRaL, and these were dimerized to mimic the bidentate interaction of homodimeric GDF15. Guided by structural data, the monomeric peptides were converted into tandem Bicycle molecules with picomolar affinities, similar to that of the endogenous GDF15 ligand. These dimerized protein mimetics inhibited cell signaling in a functional assay and showed improved pharmacokinetic properties compared with their monomeric counterparts. This is the first example of a homodimeric Bicycle molecule inhibiting receptor complex formation, thereby antagonizing the intracellular signaling response.	Oct 2025
I04-1-Macromolecular Crystallography (fixed wavelength)	Crystallographic fragment screening of the Dengue virus polymerase reveals multiple binding sites for the development of non-nucleoside antiflavivirals Manisha Saini , Jasmin C. Aschenbrenner , Francesc Xavier Ruiz , Ashima Chopra , Anu V. Chandran , Peter G. Marples , Blake H. Balcomb , Daren Fearon , Frank Von Delft , Eddy Arnold Journal Of Medicinal Chemistry 276 DOI: 10.1021/acs.jmedchem.5c01014 Diamond Proposal Number(s): [32633] Open Access Show Abstract ▼ Abstract: Dengue viruses (DENVs) infect approximately 400 million people each year, and currently, there are no effective therapeutics available. To explore potential starting points for antiviral drug development, we conducted a large-scale crystallographic fragment screen targeting the RNA-dependent RNA polymerase (RdRp) domain of the nonstructural protein 5 (NS5) from DENV serotype 2. Our screening, which involved 1108 fragments, identified 60 hit compounds across various known binding sites, including the active site, N pocket, and RNA tunnel. Additionally, we discovered a novel binding site and a fragment-binding hot spot in thumb site II. These structural findings open amenable avenues for developing non-nucleoside inhibitors and offer valuable insights for future structure-based drug design aimed at DENV and other flaviviral RdRps.	Sep 2025
I04-Macromolecular Crystallography	Discovery of AZD8421: A potent CDK2 inhibitor with selectivity against other CDK family members and the human kinome Avipsa Ghosh , Afshan Ahmed , Konstantina Amoiradaki , Amber Y. S. Balazs , Bernard Barlaam , Michael S. Bodnarchuk , Gavin W. Collie , Ian L. Dale , Christopher R. Denz , Lisa Drew , Scott D. Edmondson , Jun Fan , Stephen Fawell , Frederick W. Goldberg , Ariamala Gopalsamy , Michael Grondine , Grace Guo , Sudhir M. Hande , Holia Hatoum-Mokdad , Alexander W. Hird , Rachel Howells , Jessie Hao-Ru Hsu , Jessica Hudson , Anne Jackson , Michelle L. Lamb , Gillian M. Lamont , Scott Lamont , Phillip A. Lichtor , Lisa Mcwilliams , David Milne , Scott N. Mlynarski , Priyanka Narasimhan , Matthew F. Peters , Alexander Pflug , Hannah Kate Pollard , Meile Qin , Corinne Reimer , Kevin J. Robbins , James Robinson , Li Sha , Hongyao She , James E. Sheppeck , Baljinder Singh , Kun Song , Qibin Su , Reem Telmesani , Scott Throner , Christina Vasalou , Lei Wang , Yanjun Wang , David M. Wilson , Poppy Winlow , Wenzhan Yang , Tieguang Yao , Yun Zhang , Zirong Zhang , Diana Zindel , Jeffrey W. Johannes Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c01478 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Targeting CDK2 with first generation CDK2 inhibitors suffered from a reduced therapeutic index likely due to toxicity stemming from lack of selectivity against the CDK family and other kinases. Recently, CDK2 has been identified as a mediator of resistance to CDK4/6 inhibitors in the context of high levels of cyclin E expression. Discovery of highly selective CDK2 inhibitors may minimize off-target effects, reduce toxicity observed with first generation CDK2 inhibitors, and allow precise targeting of aberrant cell cycle progression and resistance mechanisms mediated by high cyclin E/CDK2 activity. To this end, we report the discovery of AZD8421, a potent and highly selective CDK2 inhibitor, which exhibits superior selectivity for CDK2 over CDK1, other CDK family members, and the broader human kinome. AZD8421 demonstrates favorable pharmacokinetic properties, including excellent solubility and robust in vitro stability. Demonstrated efficacy in an ovarian cancer patient-derived xenograft model further supports its potential as a therapeutic agent.	Sep 2025
I03-Macromolecular Crystallography	Design of 2-aminobenzothiazole derivatives targeting trypanosomatid PTR1 by a multidisciplinary fragment hybridization approach Joanna Panecka-Hofman , Pasquale Linciano , Ina Pöhner , Edyta Dyguda-Kazimierowicz , Wiktoria Jedwabny , Giacomo Landi , Nuno Santarem , Gesa Witt , Bernhard Ellinger , Maria Kuzikov , Rosaria Luciani , Stefania Ferrari , Daniele Aiello , Stefano Mangani , Cecilia Pozzi , Anabela Cordeiro-Da-Silva , Sheraz Gul , Maria Paola Costi , Rebecca C. Wade Journal Of Medicinal Chemistry 51 DOI: 10.1021/acs.jmedchem.5c01799 Diamond Proposal Number(s): [15832] Open Access Show Abstract ▼ Abstract: Pteridine reductase 1 (PTR1) is a folate pathway enzyme essential for pathogenic trypanosomatids and a promising drug target for diseases such as sleeping sickness and leishmaniasis. Previous studies have shown that the 2-aminobenzothiazole moiety targets the PTR1 biopterin pocket, while 3,4-dichlorophenyl-containing compounds, such as I bind a different region of the Trypanosoma brucei PTR1 (TbPTR1) pocket. This study combines both moieties via various linkers, creating two compound series screened in silico against TbPTR1 and Leishmania major PTR1 (LmPTR1). In the first series, five compounds were synthesized, and 1a and 1b emerged as potent TbPTR1 inhibitors, with 1b also being active against LmPTR1 and moderately effective against Leishmania infantum. Furthermore, structure–activity relationship analysis, supported by quantum calculations and crystallography, revealed meta-halogenation to be more favorable than para, although single halogenation reduced antiparasite effects. Our fragment hybridization approach led to less toxic, more effective compounds than I.	Sep 2025
I02-Macromolecular Crystallography	Discovery of a novel series of iso-indolinone-based glutarimides as highly efficacious and selective IKZF2 molecular glue degraders Xuqing Zhang , Harshil Dhruv , Qiaolin Deng , Matthew Tudor , Nelisa Bechtel , Rakesh Nagilla , Larry Jolivette , Cory T. Rice , Peter Orth , Elham Behshad , Corey Strickland , Helai P. Mohammad , Longchuan Bai , Donna Mceachern , Shaomeng Wang , Zhihua Sui , E. Scott Priestley Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c00668 Show Abstract ▼ Abstract: Immunosuppressive Tregs, regulated by IKZF2 (Helios), promote tumor immune evasion and resistance to immune checkpoint therapies (ICTs). Targeting IKZF2 degradation offers a promising cancer immunotherapy approach. We developed a novel series of iso-indolinone-based glutarimides, identifying compound 55 as a potent, selective IKZF2 degrader with >90% Dmax in Jurkat cells, outperforming benchmarks DKY709 and PVTX-405. It exhibits strong selectivity over IMiD neo-substrates, favorable solubility, metabolic stability, and oral bioavailability in rodents. PK/PD studies confirmed profound, persistent IKZF2 degradation in mouse spleen and thymus after a single oral dose. As a promising early-stage tool, 55 provides a foundation for further preclinical evaluation in cancer immunotherapy.	Aug 2025

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