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405 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
I04-Macromolecular Crystallography	Discovery of thiobarbiturate-indole scaffold as a selective inhibitor targeting chikungunya virus nsP3 macrodomain through a cryptic binding pocket Men Thi Hoai Duong , Tomi A. O. Parviainen , Aditya Thiruvaiyaru , Tero Ahola , Juha P. Heiskanen , Lari Lehtio European Journal Of Medicinal Chemistry 318 DOI: 10.1016/j.ejmech.2026.119182 Diamond Proposal Number(s): [34182] Open Access Show Abstract ▼ Abstract: Chikungunya virus (CHIKV) outbreaks impose significant burdens on healthcare systems and raise an urgent need for effective antiviral therapies. So far there are no specific drugs against CHIKV infection. CHIKV-encoded macrodomain is critical for virulence and counteracts the host immune response, representing a promising antiviral drug target. Here, we describe small molecule inhibitors targeting the CHIKV macrodomain. Compound 1 (MDOLL-0273) was identified through a high-throughput screening using a fluorescence resonance energy transfer based assay, exhibiting an IC50 of 8.9 μM, and its inhibitory activity was validated through multiple orthogonal assays. The compound features a thiobarbiturate-indole scaffold and shows high selectivity over a panel of human and viral ADP-ribose binding and hydrolyzing proteins. X-ray crystallography revealed that the inhibitor occupies an adenine binding site of the macrodomain and extends into a novel cryptic pocket. Guided by structure-activity relationship studies, compound 11 (MDOLL-0591) of the developed series with similar IC50 of 10 μM but with increased lipophilicity was discovered to have antiviral activity against CHIKV in cell culture, demonstrating that macrodomain could be targeted in virus infections.	Nov 2026
I04-Macromolecular Crystallography	Identification of novel CLK1 inhibitors by computational fragment-based ligand design, co-crystallization, chemical synthesis and structure activity relationships Stéphane Bourg , Matthieu Place , Chloé Copin , Apirat Chaikuad , Thomas Robert , Hanna Holzmann , Susanne Müller , Stéphane Bach , Sandrine Ruchaud , Stefan Knapp , Frédéric Buron , Sylvain Routier , Pascal Bonnet European Journal Of Medicinal Chemistry 315 DOI: 10.1016/j.ejmech.2026.118977 Open Access Show Abstract ▼ Abstract: CLK1 is one of the four human isoforms of the cdc2-like (CLK) kinases that has been suggested as a therapeutic target in diverse diseases based on its important role regulating mRNA splicing. For example, CLKs and closely related kinases such as DYRK1A have been targeted in Alzheimer’s disease and other diseases in which splice site selection contributes to the disease development. Here we have developed an efficient in silico fragment-based ligand design approach to identify novel CLK1 inhibitors with excellent ligand efficiency based on an imidazo[2,1-b][1,3,4]thiadiazole fragment. More than one million docking poses were generated from 26,225 unique virtual compounds, and after applying several filtering steps, 11 compounds were selected, synthesized and their CLK1 inhibition and cellular potency were evaluated. Gratifyingly, inhibitor potencies were in excellent agreement with predicted values and crystallographic data of an inhibitor bound to CLK1 confirmed the unusual binding mode of the compounds.	Oct 2026
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery and optimization of novel nonhydroxamate LpxC inhibitors for the treatment of multidrug-resistant gram-negative infections David P. Martin , Min Teng , Baskar Nammalwar , Christian Perez , Xiaoming Li , Jason Munguia , Konstantin Taganov , Junhua Fan , Sanjay Agarwalla , David Lonergan , Andrew P. Tomaras , Zachary Zimmerman , David T. Puerta Journal Of Medicinal Chemistry 399 DOI: 10.1021/acs.jmedchem.6c01036 Open Access Show Abstract ▼ Abstract: This report summarizes the discovery and optimization of a novel series of nonhydroxamate inhibitors targeting LpxC, a Zn2+-dependent hydrolase that is essential for the survival of Gram-negative bacteria. Beginning with a 5-hydroxypyrimidin-4-one metal-binding pharmacophore, structure-based approaches were utilized to generate a series of potent inhibitors that exhibited activity against a wide variety of Enterobacterales, including both susceptible and multidrug-resistant pathogens, and efficacy in murine thigh infection models. These novel compounds were evaluated in a rat model of cardiovascular toxicity to demonstrate the safety of the scaffold relative to another LpxC inhibitor that proved unsuccessful in Phase I clinical trials. A variety of inhibitors with potent in vivo efficacy and no hemodynamic effects were identified, which constituted an initial suite of potential development candidates.	Aug 2026
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Fragment-based discovery of potent RNA-competitive inhibitors of the DEAH-Box RNA helicase DHX8 Benjamin J. Read , Caroline Ewens , Federica Gigante , Jemima Thomas , Catarina Felisberto-Rodrigues , Silvia Alvarez Peres , Christopher Tighe , Edgar De Las Heras Ruiz , Kai Schiemann , Andrew G. Malcolm , Peter . Mcandrew , Mark Stubbs , Harshnira Patani , Helena Dos Santos Costa , Katharine Stoodley , Lisa Pickard , Michael Busch , Emma Gunnell , Sara Silva , Alexandra Knopp , Stephen Hallett , Martin Augustin , Alfred Lammens , Michael Carter , Mirco Meniconi , Marco Ballarotto , Jon Ainsley , Paul Meister , Debarati Sethi , Rosemary Burke , Andrea Scarpino , Yann-Vai Le Bihan , Ulrich Grädler , Julian Blagg , Paul Workman , Paul A. Clarke , Andreas Blum , Christina Esdar , Gurdip Bhalay , Rob L. M. Van Montfort Journal Of Medicinal Chemistry 14 DOI: 10.1021/acs.jmedchem.6c00732 Open Access Show Abstract ▼ Abstract: Human DHX8 is a spliceosomal DEAH-box RNA helicase involved in releasing mRNA from the spliceosome and crucial in ensuring splicing fidelity. DHX8 was identified as a promising therapeutic oncology target due to its role in regulating stress-adaptive gene expression, including HSF1-dependent transcription, while having broader transcriptional effects in cells under oncogenic stress. We report the discovery of novel RNA-competitive DHX8 inhibitors based on a 2-(phenethylthio)nicotinic acid scaffold, which were optimized using a structure-guided design approach, following a biophysical fragment screen. This yielded compound 53 with nanomolar biochemical potency, good in vitro PK, and activity in a cellular target engagement assay. Optimizing inhibitor binding between Arg647 and the nonconserved His693, coupled with extending into a pocket in the DHX8 Winged-Helix domain, was crucial for potency improvement. By binding in the Winged-Helix domain, these inhibitors restrict the helicase domain’s conformational plasticity, stabilizing a closed, inactive conformation while sterically blocking ssRNA translocation.	Aug 2026
I04-1-Macromolecular Crystallography (fixed wavelength)	X-ray crystallography-guided design and synthesis of cyclopentyl heteroaryl carboxylic acid-based inhibitors of the SARS-CoV-2 Nsp3 macrodomain (Mac1) Xinyu Wang , William T. W. Butler , James R. Donald , Yuran Wang , Alice L. Shaw , Marion Schuller , Daren Fearon , Jasmin C. Aschenbrenner , Peter G. Marples , Grant Watt , Yang Lu , Simon C. C. Lucas , Silvia Bonomo , Jennifer E. Nelson , Ivan Ahel , Frank Von Delft , Peter O'Brien Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6c00236 Diamond Proposal Number(s): [27001] Open Access Show Abstract ▼ Abstract: Mac1 is a conserved macrodomain enzyme in the nonstructural protein 3 (Nsp3) of SARS-CoV-2 and is part of the viral replication machinery. Mac1 is a target for small-molecule inhibitors that could ultimately enable new COVID-19 therapeutics to be developed. Here, we report the structure-guided design, synthesis, and Mac1 inhibition profiling of 25 analogues derived from a hit identified through crystallographic fragment screening. The heteroaryl group and scaffold (cis- and trans-cyclopentane and cyclopentene) were varied. Two new approaches to trans-cyclopentanes were developed: MacMillan’s Ir/Ni-mediated photoredox cross-coupling of alcohols and Barluenga–Valdés’ metal-free cross-coupling of sulfonyl hydrazones and boronic acids. X-ray crystal structures of 19 compounds bound to Mac1 were determined to guide the design and to rationalize the observed SAR. A new family of Mac1 inhibitors with benzothiazole or amino benzothiazoles was discovered and characterized, with IC50 values of 6–8 μM and ligand efficiency values of up to 0.40.	Jul 2026
I03-Macromolecular Crystallography	Discovery of potent and orally bioavailable diaminoquinazoline-derived mRNA decapping scavenger (DcpS) enzyme inhibitors for treatment of solid tumors Spencer O. Scholz , Alexander S. Dudnik , Aristidis Vasilopoulos , Zhaozhong J. Jia , Anna Albertson , Brian S. Brown , Liye Chen , Renhe Li , Gaoyuan Ma , Longcheng Wang , Akinori Okano , Xianrui Zhao , Xingyu Jiang , Caleb Karmel , Patrick B. Brady , Chunqiu Lai , Hemantkumar Deokar , Felix Deanda , Somdutta Roy , Manasi Mayekar , Hana Choi , Louis Lin , David G. Belair , Anand Joshi , Woo Hyun Yoon , Andrea Montano , Xiaoping Xie , Henry Nguyen , Haiyan S. Li , Chin Pan , Ben Danna , Deepak Gurbani , Jingzhi Li , Alla Korepanova , Tao Li , Tarikere Gururaja , Rong-Xian Ding , Rinku Jain , Ruth L. Martin , Rebecca Kohnken , Alexey Rivkin Journal Of Medicinal Chemistry 21 DOI: 10.1021/acs.jmedchem.6c01711 Show Abstract ▼ Abstract: Decapping Scavenger (DcpS) enzyme, a pyrophosphatase involved in mRNA regulation via mRNA cap degradation, has been identified as a promising oncology target in fragile histidine triad (FHIT) deficient cancers such as AML and GBM but remains underexplored in broader solid tumor indications. We have discovered a novel DcpS inhibitor, compound 17, which has a differentiated binding mode relative to known inhibitors, engaging the second nucleotide-binding domain of the mRNA cap substrate. Compound 17 possesses superior levels of potency in NSCLC A549 cell line relative to known inhibitors and demonstrates excellent selectivity against DcpS-insensitive cell lines, high levels of bioavailability in preclinical species, and mitigated hERG liabilities. Finally, compound 17 demonstrates oral dose-dependent efficacy in two solid tumor xenograft models, A253 and EBC-1, highlighting the promise of DcpS as a novel target in FHIT low/deficient solid tumors.	Jul 2026
I04-Macromolecular Crystallography	Generative AI-assisted discovery of HPK1 inhibitors Kathryn A. Giblin , Kun Song , Hongming Chen , Weijie Chen , Zhiqiang Dong , Randolph A. Escobar , Tyler P. Grebe , Neil P. Grimster , Alexander W. Hird , Samantha J. Hughes , Jason G. Kettle , Chengzhi Li , Hao Ma , Alexander Pflug , Magdalena Richter , Marianne Schimpl , Haoran Tang , Peng Wang , Gail Wrigley , Ye Wu , Haichang Yu , Robert E. Ziegler , Jason D. Shields Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.6c01048 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Generative artificial intelligence (AI) is now widely applied in medicinal chemistry, with detailed case studies emerging in the literature. Here, we describe an early application of REINVENT, AstraZeneca’s in-house generative molecular design platform, to identify new inhibitor scaffolds for hematopoietic progenitor kinase 1 (HPK1). REINVENT was deployed at two stages of the project to address distinct design objectives. For hit identification, transfer learning on kinase-active compounds, followed by reinforcement learning guided by QSAR-based scoring, led to the discovery of three active chemotypes. Subsequently, REINVENT was applied to scaffold hopping, using 3D pharmacophore and docking models as scoring functions, which enabled the identification of two additional active chemotypes. Optimization of one of these scaffolds delivered a compound with potent cellular activity, kinase selectivity, and favorable rat pharmacokinetics. These results demonstrate the value of integrating generative AI with medicinal chemistry expertise and support broader application of the approach in future discovery programs.	Jul 2026
I03-Macromolecular Crystallography	Structure-guided optimization of novel inhibitors of Plasmodium lysyl-tRNA synthetase with multistage activity against malaria parasites Barbara Forte , Fiona Bellany , Peter S. Campbell , Giulia Chemi , Alice Dawson , Mark Anderson , Yaw Aniweh , Anna Y. Burkhard , Anna Caroline Campos Aguiar , Alisje Churchyard , Caitlin A. Cooper , Amália Dos Santos Ferreira , Mufuliat Toyin Famodimu , Francis G. Fang , Xiao Hu , Tonnie Huijs , Delphine Baud , Chimed Jansen , María Belén Jiménez Díaz , Roger Bonnert , Susan Boyd , Benigno Crespo-Fernández , Branko Mitasev , Simone Montagna , Sachel Mok , Dinakaran Murugesan , Sunil K. Narwal , Neil R. Norcross , John Okombo , Heekuk Park , Caroline Peet , Dhelio B. Pereira , John M. Post , Janette Reader , Jennifer Riley , David A. Robinson , Raku Shinkyo , Frederick R. C. Simeons , Laura Simpson , Alasdair Smith , Dennis Smith , Josefine Striepen , Carolina B. G. Teles , Rianne Van Der Laak , Anne-Catrin Uhlemann , Amélie Vantaux , Caroline Wilson , Benoît Witkowski , Gavin Wood , Tomas Yeo , Fabio Zuccotto , Iñigo Angulo-Barturen , Jake Baum , Judith M. Bolscher , Rafael Victorio Carvalho Guido , Lyn-Marié Birkholtz , Michael J. Delves , Laurent Dembele , David A. Fidock , Francisco Javier Gamo , Dennis E. Kyle , Steven P. Maher , Jean Popovici , Chris Walpole , Fabian Gusovsky , Paul A. Willis , Kevin D. Read , Ian H. Gilbert , Beatriz Baragaña Journal Of Medicinal Chemistry 45 DOI: 10.1021/acs.jmedchem.6c00823 Diamond Proposal Number(s): [10071, 26793] Open Access Show Abstract ▼ Abstract: A fused dihydropyrrolidino-pyrimidine hit with low lipophilicity and excellent ligand efficiency was identified in a biochemical screen of the Global Health Chemical Diversity Library (GHCDL) against Plasmodium lysyl-tRNA synthetase (KRS). Structure-guided lead optimization delivered analogues with potent parasite growth inhibition, excellent biochemical and cellular selectivity (>1000-fold), and oral efficacy in the malaria NOD-scid-IL2Rγnull (SCID) mouse model. Structural information and computational methods were deployed to identify a potent and selective basic KRS inhibitor (30) with an extended half-life to reduce the dose regimen to a single-dose cure. Compound 30 displayed a long half-life across preclinical species, favorable safety, and activity across Plasmodium species as well as against drug-resistant and sensitive P. falciparum strains and field isolates. Unfortunately, 30 lacked oral bioavailability, which could not be mitigated with a prodrug approach. Nevertheless, learnings from this series will assist future KRS programs in delivering a clinical candidate with this novel mode of action.	Jun 2026
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure-based discovery of potent BCL-XL inhibitors through rescaffolding Matyas Pal Timari , Attila Paczal , Andras Herner , Mark Molnar , Zoltan Madarasz , Miklos Nyerges , Simon T. Bedford , Teresa Brooks , James Davidson , Zoe Daniels , Mark Dodsworth , Pawel Dokurno , James B. Murray , Rachel Parsons , Emma Sanders , Julia Smith , Paul Webb , Neil Whitehead , Roderick E. Hubbard , Jérôme-Benoît Starck , Ana Leticia Maragno , Gaëtane Le Toumelin-Braizat , Laura Bresson , Francesca Rocchetti , Didier Demarles , Frédéric Colland , Olivier Geneste , Andras Kotschy , Tibor Novak Journal Of Medicinal Chemistry 60 DOI: 10.1021/acs.jmedchem.6c00865 Diamond Proposal Number(s): [5067, 12428, 14601] Open Access Show Abstract ▼ Abstract: Evasion of apoptosis is a hallmark of cancer. Deregulation of BCL-XL, a member of the BCL-2 family of proteins, has been linked to the development of various tumor types. This study presents the design and synthesis of BCL-XL inhibitors with novel mono- and bicyclic cores. The new structural features were optimized to combine high binding efficiency with the opening of diverse novel vectors for additional modifications. The lead compounds exhibited picomolar affinities and significant cellular potency in the BCL-XL-dependent MOLT-4 cell line, which also translated into marked tumor growth inhibition in a xenograft study. These findings highlight the potential of BCL-XL inhibitors as therapeutic agents in cancer treatment by targeting the apoptotic intrinsic pathway.	Jun 2026
I04-Macromolecular Crystallography	Discovery of CNS penetrant SOS1 inhibitors for the treatment of KRAS-dependent cancers Sharan K. Bagal , Coura R. N. Diène , Sandra Stefanovic-Barrett , Jason Breed , Gregory W. Kauffman , Michael S. Bodnarchuk , Gavin W. Collie , Anna D. Staniszewska , Abhishek Srivastava , Elsa Irving , Doyle J. Cassar , Sean Gray , Craig Hughes , Jason G. Kettle , Samuel Nash , Sarah Northall , Alison Peter , Markus Schade , Christopher J. Stubbs , Aaron Smith , Lucy Young Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5c03800 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kpu,u. Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRASG12C inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRASG12C inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.	Jun 2026

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