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Instruments / Technical Area	Publication Details	Published
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	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
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
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
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-ones: Studies towards the identification of potent, cell penetrant Jumonji C domain containing histone lysine demethylase 4 subfamily (KDM4) inhibitors, compound profiling in cell-based target engagement assays Yann-Vai Le Bihan , Rachel M. Lanigan , Butrus Atrash , Mark G. Mclaughlin , Srikannathasan Velupillai , Andrew G. Malcolm , Katherine S. England , Gian Filippo Ruda , N. Yi Mok , Anthony Tumber , Kathy Tomlin , Harry Saville , Erald Shehu , Craig Mcandrew , Leanne Carmichael , James M. Bennett , Fiona Jeganathan , Paul Eve , Adam Donovan , Angela Hayes , Francesca Wood , Florence I. Raynaud , Oleg Fedorov , Paul Brennan , Rosemary Burke , Rob Van Montfort , Olivia W. Rossanese , Julian Blagg , Vassilios Bavetsias European Journal Of Medicinal Chemistry DOI: 10.1016/j.ejmech.2019.05.041 Diamond Proposal Number(s): [20145] Open Access Show Abstract ▼ Abstract: Residues in the histone substrate binding sites that differ between the KDM4 and KDM5 subfamilies were identified. Subsequently, a C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one series was designed to rationally exploit these residue differences between the histone substrate binding sites in order to improve affinity for the KDM4-subfamily over KDM5-subfamily enzymes. In particular, residues E169 and V313 (KDM4A numbering) were targeted. Additionally, the conformational restriction of the flexible pyridopyrimidinone C8-substituent was investigated. These approaches yielded potent and cell-penetrant dual KDM4/5-subfamily inhibitors including 19a (KDM4A and KDM5B Ki = 0.004 and 0.007 μM, respectively). Compound cellular profiling in two orthogonal target engagement assays revealed a significant reduction from biochemical to cell-based activity across multiple analogues; this decrease was shown to be consistent with 2OG competition, and suggest that sub-nanomolar biochemical potency will be required with C8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one compounds to achieve sub-micromolar target inhibition in cells.	May 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	8-substituted pyrido[3,4-d]pyrimidin-4(3H)-one derivatives as potent, cell permeable, KDM4 (JMJD2) and KDM5 (JARID1) histone lysine demethylase inhibitors Vassilios Bavetsias , Rachel M. Lanigan , Gian Filippo Ruda , Butrus Atrash , Mark G. Mclaughlin , Anthony Tumber , N. Yi Mok , Yann-Vaï Le Bihan , Sally Dempster , Katherine J. Boxall , Fiona Jeganathan , Stephanie B. Hatch , Pavel Savitsky , Velupillai Srikannathasan , Tobias Krojer , Katherine S. England , Jimmy Sejberg , Ching Thai , Adam Donovan , Akos Pal Journal Of Medicinal Chemistry 55 (1) DOI: 10.1021/acs.jmedchem.5b01635 PMID: 26741168 Open Access Show Abstract ▼ Abstract: We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay.	Jan 2016

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