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846 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
B23-Circular Dichroism	Ligand-receptor interactions of V-domain Ig-containing suppressor of T cell activation and programmed death-1 suppress the anti-cancer activities of T cells Maryam Abooali , Xi Lei , Inna M. Yasinska , Stephanie Schlichtner , Rohanah Hussain , Giuliano Siligardi , Tiberiu-Marius Gianga , Steffen M. Berger , Dietmar Cholewa , Bernhard F. Gibbs , Elizaveta Fasler-Kan , Vadim V. Sumbayev Immuno-Oncology And Technology DOI: 10.1016/j.iotech.2025.101533 Diamond Proposal Number(s): [36941, 38189] Open Access Show Abstract ▼ Abstract: Background: VISTA is a unique multifunctional immune checkpoint protein, which can display both receptor and ligand properties. It plays a crucial role in the cancer immune evasion machinery operated by a wide range of human malignancies and may thus be considered as a potential target for immunotherapy of cancer. Receptors of VISTA through which this protein transmits immunosuppressive signals under various normal and pathological conditions remain to be identified. Materials and Methods: To conduct the study, we used human recombinant proteins and various human cell lines as well as primary T cells. A wide range of techniques including tissue culture and co-cultures, Western blot analysis, on-cell Western, ELISA, co-immunoprecipitation, biochemical assays and synchrotron radiation circular dichroism spectroscopy were employed. Results: Here we report for the first time that VISTA has affinity to PD-1 and binds it as a ligand. We found that when interacting with PD-1, VISTA suppresses IL-2 production by T helper cells. These effects were confirmed in the in vitro and ex vivo experiments. Affinity of VISTA to PD-1 was also characterised and found to be moderate, with a Kd of approximately 2.3 μM detected by synchrotron radiation circular dichroism spectroscopy. Conclusions: These results open a completely new chapter in our understanding of the concept of immune checkpoint proteins, where some of them clearly show both ligand and receptor activities and display multifunctional properties.	Nov 2025
I04-Macromolecular Crystallography	Use of direct-to-biology strategies for the discovery of 2′-deoxynucleoside 5′-monophosphate N-glycosidase (DNPH1) PROTACs Niall A. Anderson , Bernard Barlaam , Argyrides Argyrou , Peter C. Astles , Hanna Bruss , Elaine B. Cadogan , Luca Carlino , Luz Alonso-Crisostomo , Gavin W. Collie , Alex J. Edwards , Anastasiia Gryniukova , James Hall , Kunzah Jamal , Joshua Kent , Linda Kitching , Christopher Kourra , Carolyn Lam , Alexander G. Milbradt , Jenni Nikkilä , Sarah Northall , Mark J. O’connor , Jeroen Overman , Claudio Pathe , Wendy Savory , Daniel Slade , Jonathan A. Spencer , Darren Stead , Christopher J. Stubbs , Benjamin C. Whitehurst , Sabrina Winfield Journal Of Medical Chemistry 68 DOI: 10.1021/acs.jmedchem.5c02337 Diamond Proposal Number(s): [20015] Show Abstract ▼ Abstract: 2′-Deoxynucleoside 5′-monophosphate N-glycosidase (DNPH1) has emerged as an attractive target for cancer therapeutics exploiting DNA damage response pathways, yet chemical degraders for interrogating DNPH1 biology are lacking. We report the accelerated discovery of potent DNPH1 PROTACs using a direct-to-biology synthesis and screening platform. We employed miniaturized, array-based chemistry to generate a broad library of quinazoline-based PROTACs capable of recruiting a variety of different E3 ligases. Screening crude reaction mixtures in a cellular degradation assay enabled rapid identification of multiple nanomolar DNPH1 PROTACs, exemplified by compound 59, which achieved near-complete DNPH1 degradation and demonstrated strong functional activity in BRCA1 mutant cell lines. Mechanistic studies confirmed selective, proteasome- and VHL-dependent protein knockdown and recapitulation of phenotypic outcomes observed with DNPH1 genetic loss, including sensitization to hmdU treatment. Our findings highlight the power of D2B methodology to streamline PROTAC development and establish quinazoline-based degraders as robust chemical tools to advance DNPH1-targeted cancer research.	Nov 2025
I03-Macromolecular Crystallography	High-affinity peptide-drug conjugate ligands for the TRIM24 PHD and bromodomain Michael A. Platt , Ekaterina Kot , Louise A. W. Martin , Antoine L. D. Wallabrègue , Liwen Song , Alistair M. Boyd , Lizbe Koekemoer , Ester M. Hammond , Stuart J. Conway Chemistry - A European Journal DOI: 10.1002/chem.202503011 Open Access Show Abstract ▼ Abstract: TRIM24 is an epigenetic transcriptional coregulator that “reads” KMe3 and KAc histone modifications via its tandem plant homeodomain (PHD) and bromodomain (BRD), respectively. The PHD and BRD are potential therapeutic targets due to the roles of TRIM24 in breast cancer progression. However, there are currently no small-molecule ligands for the PHD, and existing TRIM24 BRD inhibitors lack selectivity over the main off-target, BRPF1. Here, we report the development of the first bivalent tool molecules capable of simultaneously engaging both the TRIM24 PHD and BRD. Key to this strategy was the identification of effective KMe3 bioisosteres that enhance H3 peptide binding to the TRIM24 PHD. The most promising of these was incorporated into a nine amino acid H3-mimicking peptide, and linked to a TRIM24 BRD ligand. The resulting peptide-drug conjugates (PDCs) bind to TRIM24 with picomolar affinity and a slow dissociation rate (koff), which is driven by an in cis bivalent binding mode. Although the PDCs showed limited effects on breast cancer cell proliferation in vitro, this work underscores their potential as tools for studying previously unliganded reader domains and consequently advancing our understanding of multivalent epigenetic regulation in disease.	Nov 2025
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery and optimization of a non-nucleoside-based series of inhibitors of 2′-deoxynucleoside 5′-monophosphate glycosidase (DNPH1) Bernard Barlaam , Luz Alonso-Crisostomo , Niall A. Anderson , Argyrides Argyrou , Peter C. Astles , Elaine B. Cadogan , Luca Carlino , Gavin W. Collie , Nichola L. Davies , James Hall , Linda Kitching , Xianxi Li , Filippos Michopoulos , Alexander G. Milbradt , Jenni Nikkilä , Sarah Northall , Mark J. O'Connor , Xiaohiu Pei , Joseph Shaw , Danial Slade , Harriet Southgate , Darren Stead , Christopher J. Stubbs , Benjamin C. Whitehurst , Bin Xing , Yihao Yuan , Jie Zhou Journal Of Medical Chemistry DOI: 10.1021/acs.jmedchem.5c02356 Show Abstract ▼ Abstract: DNPH1 is a nucleotide pool sanitizer that cleaves 5-hydroxymethyl-2-deoxyuridine-5-monophosphate (hmdUMP), preventing incorporation of the correspondent non-natural nucleotide into DNA. Recent findings have demonstrated that loss of DNPH1 could potentiate the sensitivity of PARP inhibitors in homologous recombination repair (HRR)-deficient cancers. We report the optimization of a non-nucleoside-based series of DNPH1 inhibitors. Starting from a weak compound 1 (binding affinity pIC50 4.7), we identified compound 38 as a very potent inhibitor of DNPH1 (pIC50 9.3) using DNPH1 X-ray structure-guided drug design. Compound 38 demonstrated target engagement of DNPH1 in the SUM149PT cell line (pIC50 7.2). Using this tool compound, we then report the in vitro pharmacology of a DNPH1 inhibitor in the BRCA1 mutant SUM149PT cell line.	Nov 2025
I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of first-in-class inhibitors of the TRF1:TIN2 protein:protein interaction by fragment screening Giacomo Casale , Manjuan Liu , Yann-Vai Le Bihan , Oviya Inian , Ellie Stammers , John Caldwell , Rob Van Montfort , Ian Collins , Sebastian Guettler Scientific Reports 15 DOI: 10.1038/s41598-025-23858-3 Diamond Proposal Number(s): [26617] Open Access Show Abstract ▼ Abstract: TRF1 is a subunit of the shelterin complex that binds to and protects the linear ends of chromosomes known as telomeres. Both genetic deletion and chemical inhibition of TRF1 have been shown to block the growth of lung carcinoma, glioblastoma, and renal cell carcinoma in mice without affecting mouse survival or tissue function, making TRF1 a potential therapeutic target in cancer1,2,3. Here, we report the discovery of a series of fragment hits that bind at the interface between the TRFH domain of TRF1 (TRF1TRFH) and a peptide of TIN2 (TIN2TBM), an interaction essential for the recruitment of TRF1 to shelterin, using X-ray crystallography (XChem) and ligand-observed NMR (LO-NMR) fragment screening. We discovered a first-in-class inhibitor of the TRF1:TIN2 interaction (compound 40) that binds to TRF1TRFH with a KD of 29 µM (95% CI: 20–41 µM), displaces a TIN2 probe with an IC50 of 67 µM (95% CI: 10–120 µM), and expels TRF1 from purified shelterin. Aided by a novel crystal system of TRF1TRFH, we characterised fragments binding in a hotspot at the TRF1:TIN2 interface; these will serve as a starting point for the structure-guided development of potent inhibitors of TRF1 protein:protein interactions to disrupt shelterin complex assembly.	Nov 2025
I03-Macromolecular Crystallography	Discovery of a bifunctional PKMYT1-targeting PROTAC empowered by AI-generation Yazhou Wang , Xiaomin Wang , Tingting Liu , Chao Wang , Qingshuo Meng , Fanye Meng , Jiaojiao Yu , Jinxin Liu , Yaya Fan , David Gennert , Frank W. Pun , Alex Aliper , Feng Ren , Man Zhang , Xin Cai , Xiao Ding , Alex Zhavoronkov Nature Communications 16 DOI: 10.1038/s41467-025-65796-8 Open Access Show Abstract ▼ Abstract: PKMYT1 has recently emerged as a compelling therapeutic target for precision cancer therapy due to its synthetic lethality with oncogenic alterations such as CCNE1 amplification and mutations in FBXW7 and PPP2R1A. Current small molecule PKMYT1 inhibitors face limitations, such as insufficient molecular diversity and poor selectivity. We herein use our generative AI platform to develop a bifunctional PKMYT1 degrader by linking an entirely novel PKMYT1 inhibitor to an optimized cereblon (CRBN) binder. The lead PROTAC D16-M1P2 demonstrates dual mechanisms of PKMYT1 degradation and inhibition, with strong antiproliferative potency facilitated by high selectivity. It also exhibits favorable oral bioavailability, stronger pharmacodynamic effects relative to the PKMYT1 inhibitor alone, and robust antitumor response as a monotherapy in xenograft models. This PROTAC serves as a precise chemical probe to explore PKMYT1 biology and a promising lead for further cancer therapy exploration.	Nov 2025
I24-Microfocus Macromolecular Crystallography	Development of DARPin T cell engagers for specific targeting of tumor-associated HLA/peptide complexes Natalia Venetz-Arenas , Tim Schulte , Sandra Müller , Karin Wallden , Stefanie Fischer , Tom Resink , Nadir Kadri , Maria Paladino , Nicole Pina , Filip Radom , Denis Villemagne , Sandra Bruckmaier , Andreas Cornelius , Tanja Hospodarsch , Evren Alici , Hans-Gustaf Ljunggren , Benedict J. Chambers , Xiao Han , Renhua Sun , Marta Carroni , Victor Levitsky , Tatyana Sandalova , Marcel Walser , Adnane Achour Iscience DOI: 10.1016/j.isci.2025.113926 Diamond Proposal Number(s): [21625] Open Access Show Abstract ▼ Abstract: The balance between affinity and specificity in T cell receptor (TCR)-dependent targeting of HLA-restricted tumor-associated antigens presents a significant challenge for immunotherapy development. T cell engagers that circumvent these limitations are therefore of particular interest. We established a process to generate bispecific Designed Ankyrin Repeat Proteins (DARPins) that simultaneously target HLA-I/peptide complexes and CD3e. These high-affinity T cell engagers elicited CD8+ T cell activation against tumor targets with strong peptide specificity, as confirmed by X-scanning mutagenesis and functional killing assays. A cryo-EM structure of the ternary DARPin/HLA-A*0201/NY-ESO1157-165 complex revealed a rigid, concave DARPin surface spanning the full length of the peptide-binding cleft, contacting both α-helices and the peptide. The present findings reveal promising immuno-oncotherapeutic approaches and demonstrate the feasibility of rapidly developing DARPins with high affinity and specificity for HLA/peptide targets, which can be readily combined with a new generation of anti-CD3e-specific DARPins.	Nov 2025
I24-Microfocus Macromolecular Crystallography	Penetrant PKCb mutation in ATLL displays a mixed gain-of-function Sophie J. L. Brown , David C. Briggs , Patrick Costello , Hiroko Yaguchi , Charles R. M. Bangham , Peter J. Parker , Neil Q. Mcdonald Biochemical Journal DOI: 10.1042/BCJ20253384 Diamond Proposal Number(s): [39391] Open Access Show Abstract ▼ Abstract: Mutations in the T-cell receptor signalling pathway have been identified in patients with adult T-cell leukaemia/lymphoma (ATLL) and one of the most frequently observed targets of these mutations is protein kinase C beta (PKCb). Here we have characterised the most frequent mutation in PKCb (D427N) addressing the issue of gain/loss of function, neomorphic change, assessing the impact of mutation in vivo, in cells, biochemically and structurally. It is concluded that this mutation is a gain-of-function, activating mutation that confers an altered substrate specificity on this protein kinase. In a constitutive knock-in mouse model this activated allele induces splenomegaly associated with extramedullary haematopoiesis. Pharmacologically, the D427N mutant protein displays poor sensitivity to established PKCb inhibitors, necessitating development of bespoke therapeutics for any ATLL intervention through this target. Such efforts could be guided by the availability the D427N mutant-ruboxistaurin structure presented here.	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 I04-1-Macromolecular Crystallography (fixed wavelength)	AI-assisted delivery of novel covalent WRN inhibitors from a non-covalent fragment screen Geoffrey M. T. Smith , Laksh Aithani , Charlotte E. Barrett , Alwin O. Bucher , Christopher D. O. Cooper , Sébastien L. Degorce , Andrew Dore , Catherine T. Fletcher , Sophie Huber , Rosemary Huckvale , Amanda J. Kennedy , Abigail A. Mornement , Mark Pickworth , Prakash Rucktooa , Conor C. G. Scully , Sarah E. Skerratt Bioorganic & Medicinal Chemistry Letters 131 DOI: 10.1016/j.bmcl.2025.130421 Show Abstract ▼ Abstract: Werner (WRN) helicase, has emerged as a promising therapeutic target for cancers associated with microsatellite instability (MSI). This letter describes the discovery of small molecule inhibitors from a fragment screen that occupy a cryptic, allosteric site of WRN helicase. Key findings include the identification of benzimidazole and amino-indazole scaffolds, exploiting their proximity to Cys727 via covalent modification. The use of our proprietary co-folding model DragonFold assisted the identification of novel WRN helicase inhibitors. These, together with near-neighbor profiling, offer tools for furthering the understanding of WRN and BLM helicase function, and potential therapeutic avenues for MSI-associated cancers.	Oct 2025

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