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12 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I04-1-Macromolecular Crystallography (fixed wavelength)	Evaluating the impact of CRBN mutations on response to immunomodulatory drugs and novel CRBN-binding agents in myeloma Yakinthi Chrisochoidou , Andrea Scarpino , Salomon Morales , Shannon Martin , Sarah A. Bird , Yigen Li , Brian A. Walker , John Caldwell , Yann-Vai Le Bihan , Charlotte Pawlyn Blood Journal DOI: 10.1182/blood.2024025861 Diamond Proposal Number(s): [14891] Show Abstract ▼ Abstract: Immunomodulatory drug (IMiD) resistance is a key clinical challenge in myeloma treatment. Previous data suggests almost one third of myeloma patients acquire mutations in the key IMiD effector cereblon by the time they are pomalidomide refractory. Some events, including stop codons/frameshift mutations and copy loss, having clearly explicable effects on cereblon function. Missense mutations have also been reported throughout the length of cereblon but their functional impact has not been systematically studied. This study modelled selected missense mutations and examined their effect on cereblon function also analysing whether any mutations deleterious to IMiD action could be overcome using the novel cereblon binding agents (CELMoDs). Three patterns of response to missense mutations were apparent, mutations that led to complete loss of CRBN function for all agents, those that had no effect on CRBN function and those with agent-dependent effect on CRBN function. The latter group of 4 mutations were profiled in more detail with confirmatory experiments demonstrating an ability of the more potent CELMoDs to lead to neosubstrate degradation and cell death even though IMiDs were not active. Dynamic modelling based on a newly generated crystal structure of the DDB1/CRBN/lenalidomide complex, with greater resolution than those published to date, helped to understand the impact of these mutations. These results have important implications for the interpretation of CRBN sequencing results from patients for future therapy decisions, particularly differentiating those who may, despite relapsing on IMiDs with CRBN mutations, have the potential to still benefit from the use of CELMoD agents.	Jan 2025
I24-Microfocus Macromolecular Crystallography	Specific radiation damage to halogenated inhibitors and ligands in protein–ligand crystal structures Matthew Rodrigues , Marc Cabry , Gavin Collie , Michael Carter , Craig Mcandrew , Robin L. Owen , Benjamin R. Bellenie , Yann-Vai Le Bihan , Rob L. M. Van Montfort Journal Of Applied Crystallography 57, 1951 - 1965 DOI: 10.1107/S1600576724010549 Open Access Show Abstract ▼ Abstract: Protein–inhibitor crystal structures aid medicinal chemists in efficiently improving the potency and selectivity of small-molecule inhibitors. It is estimated that a quarter of lead molecules in drug discovery projects are halogenated. Protein–inhibitor crystal structures have shed light on the role of halogen atoms in ligand binding. They form halogen bonds with protein atoms and improve shape complementarity of inhibitors with protein binding sites. However, specific radiation damage (SRD) can cause cleavage of carbon–halogen (C–X) bonds during X-ray diffraction data collection. This study shows significant C–X bond cleavage in protein–ligand structures of the therapeutic cancer targets B-cell lymphoma 6 (BCL6) and heat shock protein 72 (HSP72) complexed with halogenated ligands, which is dependent on the type of halogen and chemical structure of the ligand. The study found that metrics used to evaluate the fit of the ligand to the electron density deteriorated with increasing X-ray dose, and that SRD eliminated the anomalous signal from brominated ligands. A point of diminishing returns is identified, where collecting highly redundant data reduces the anomalous signal that may be used to identify binding sites of low-affinity ligands or for experimental phasing. Straightforward steps are proposed to mitigate the effects of C–X bond cleavage on structures of proteins bound to halogenated ligands and to improve the success of anomalous scattering experiments.	Dec 2024
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	A degron blocking strategy towards improved CRL4CRBN recruiting PROTAC selectivity Habib Bouguenina , Andrea Scarpino , James O'Hanlon , Justin Warne , Hannah Z. Wang , Laura Chan Wah Hak , Amine Sadok , P. Craig Mcandrew , Mark Stubbs , Olivier A. Pierrat , Tamas Hahner , Marc P. Cabry , Yann-Vai Le Bihan , Costas Mitsopoulos , Fernando Jr. Sialana , Theodoros I. Roumeliotis , Rosemary Burke , Rob Van Montfort , Jyoti Choudhary , Rajesh Chopra , John J. Caldwell , Ian Collins Chembiochem DOI: 10.1002/cbic.202300351 Open Access Show Abstract ▼ Abstract: Small molecules inducing protein degradation are important pharmacological tools to interrogate complex biology and are rapidly translating into clinical agents. However, to fully realise the potential of these molecules, selectivity remains a limiting challenge. Herein, we addressed the issue of selectivity in the design of CRL4CRBN recruiting PROteolysis TArgeting Chimeras (PROTACs). Thalidomide derivatives used to generate CRL4CRBN recruiting PROTACs have well described intrinsic monovalent degradation profiles by inducing the recruitment of neo-substrates such as GSPT1, Ikaros and Aiolos. We leveraged structural insights from known CRL4CRBN neo-substrates to attenuate and indeed remove this monovalent degradation function in well-known CRL4CRBN molecular glues degraders, namely CC-885 and Pomalidomide. We then applied these design principles on a previously published BRD9 PROTAC (dBRD9-A) and generated an analogue with improved selectivity profile. Finally, we implemented a computational modelling pipeline to show that our degron blocking design does not impact PROTAC induced ternary complex formation. We believe that the tools and principles presented in this work will be valuable to support the development of targeted protein degradation.	Jul 2023
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)	Discovering cell-active BCL6 inhibitors: effectively combining biochemical HTS with multiple biophysical techniques, X-ray crystallography and cell-based assays Olivier A. Pierrat , Manjuan Liu , Gavin W. Collie , Kartika N. Shetty , Matthew J. Rodrigues , Yann-Vai Le Bihan , Emma A. Gunnell , P. Craig Mcandrew , Mark Stubbs , Martin G. Rowlands , Norhakim Yahya , Erald Shehu , Rachel Talbot , Lisa Pickard , Benjamin R. Bellenie , Kwai-Ming J. Cheung , Ludovic Drouin , Paolo Innocenti , Hannah Woodward , Owen A. Davis , Matthew G. Lloyd , Ana Varela , Rosemary Huckvale , Fabio Broccatelli , Michael Carter , David Galiwango , Angela Hayes , Florence I. Raynaud , Christopher Bryant , Steven Whittaker , Olivia W. Rossanese , Swen Hoelder , Rosemary Burke , Rob L. M. Van Montfort Scientific Reports 12 DOI: 10.1038/s41598-022-23264-z Open Access Show Abstract ▼ Abstract: By suppressing gene transcription through the recruitment of corepressor proteins, B-cell lymphoma 6 (BCL6) protein controls a transcriptional network required for the formation and maintenance of B-cell germinal centres. As BCL6 deregulation is implicated in the development of Diffuse Large B-Cell Lymphoma, we sought to discover novel small molecule inhibitors that disrupt the BCL6-corepressor protein–protein interaction (PPI). Here we report our hit finding and compound optimisation strategies, which provide insight into the multi-faceted orthogonal approaches that are needed to tackle this challenging PPI with small molecule inhibitors. Using a 1536-well plate fluorescence polarisation high throughput screen we identified multiple hit series, which were followed up by hit confirmation using a thermal shift assay, surface plasmon resonance and ligand-observed NMR. We determined X-ray structures of BCL6 bound to compounds from nine different series, enabling a structure-based drug design approach to improve their weak biochemical potency. We developed a time-resolved fluorescence energy transfer biochemical assay and a nano bioluminescence resonance energy transfer cellular assay to monitor cellular activity during compound optimisation. This workflow led to the discovery of novel inhibitors with respective biochemical and cellular potencies (IC50s) in the sub-micromolar and low micromolar range.	Nov 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
I24-Microfocus Macromolecular Crystallography	Discovery and characterization of a cryptic secondary binding site in the molecular chaperone HSP70 Suzanne O'Connor , Yann-Vai Le Bihan , Isaac M. Westwood , Manjuan Liu , Oi Wei Mak , Gabriel Zazeri , Ana P. R. Povinelli , Alan M. Jones , Rob Van Montfort , Jóhannes Reynisson , Ian Collins Molecules 27 DOI: 10.3390/molecules27030817 Diamond Proposal Number(s): [6385] Open Access Show Abstract ▼ Abstract: Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromolar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series.	Jan 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Into deep water: optimizing BCL6 inhibitors by growing into a solvated pocket Matthew G. Lloyd , Rosemary Huckvale , Kwai-Ming J. Cheung , Matthew J. Rodrigues , Gavin W. Collie , Olivier A. Pierrat , Mahad Gatti Iou , Michael Carter , Owen A. Davis , P. Craig Mcandrew , Emma Gunnell , Yann-Vai Le Bihan , Rachel Talbot , Alan T. Henley , Louise D. Johnson , Angela T. Hayes , Michael D. Bright , Florence I. Raynaud , Mirco Meniconi , Rosemary Burke , Rob L. M. Van Montfort , Olivia W. Rossanese , Benjamin R. Bellenie , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c00946 Diamond Proposal Number(s): [14891, 20145] Open Access Show Abstract ▼ Abstract: We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.	Nov 2021
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Achieving in vivo target depletion through the discovery and optimization of benzimidazolone BCL6 degraders Benjamin R. Bellenie , Kwai-Ming J. Cheung , Ana Varela , Olivier A. Pierrat , Gavin W. Collie , Gary M. Box , Michael D. Bright , Sharon Gowan , Angela Hayes , Matthew J. Rodrigues , Kartika N. Shetty , Michael Carter , Owen A. Davis , Alan T. Henley , Paolo Innocenti , Louise D. Johnson , Manjuan Liu , Selby De Klerk , Yann-Vai Le Bihan , Matthew G. Lloyd , P. Craig Mcandrew , Erald Shehu , Rachel Talbot , Hannah L. Woodward , Rosemary Burke , Vladimir Kirkin , Rob L. M. Van Montfort , Florence I. Raynaud , Olivia W. Rossanese , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.9b02076 Diamond Proposal Number(s): [14891, 20145] Open Access Show Abstract ▼ Abstract: Deregulation of the transcriptional repressor BCL6 enables tumorigenesis of germinal center B-cells, and hence BCL6 has been proposed as a therapeutic target for the treatment of diffuse large B-cell lymphoma (DLBCL). Herein we report the discovery of a series of benzimidazolone inhibitors of the protein-protein interaction between BCL6 and its co-repressors. A subset of these inhibitors were found to cause rapid degradation of BCL6, and optimization of pharmacokinetic properties led to the discovery of 5-((5-chloro-2-((3R,5S)-4,4-difluoro-3,5-dimethylpiperidin-1-yl)pyrimidin-4-yl)amino)-3-(3-hydroxy-3-methylbutyl)-1-methyl-1,3-dihydro-2H-benzo[d]imidazol-2-one (CCT369260), which reduces BCL6 levels in a lymphoma xenograft mouse model following oral dosing.	Apr 2020

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