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Instruments / Technical Area	Publication Details	Published
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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