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

Instruments / Technical Area	Publication Details	Published
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
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
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
I04-1-Macromolecular Crystallography (fixed wavelength)	Introduction of a methyl group curbs metabolism of pyrido[3,4- d ]pyrimidine monopolar spindle 1 (mps1) inhibitors and enables the discovery of the phase 1 clinical candidate.. Hannah L. Woodward , Paolo Innocenti , Kwai-Ming J. Cheung , Angela Hayes , Jennie Roberts , Alan T. Henley , Amir Faisal , Grace Wing-Yan Mak , Gary Box , Isaac M. Westwood , Nora Cronin , Michael Carter , Melanie Valenti , Alexis De Haven Brandon , Lisa O’fee , Harry Saville , Jessica Schmitt , Rosemary Burke , Fabio Broccatelli , Rob L. M. Van Montfort , Florence I. Raynaud , Suzanne A. Eccles , Spiros Linardopoulos , Julian Blagg , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00690 Diamond Proposal Number(s): [10088] Open Access Show Abstract ▼ Abstract: Monopolar spindle 1 (MPS1) occupies a central role in mitosis and is one of the main components of the spindle assembly checkpoint. The MPS1 kinase is an attractive cancer target, and herein, we report the discovery of the clinical candidate BOS172722. The starting point for our work was a series of pyrido[3,4-d]pyrimidine inhibitors that demonstrated excellent potency and kinase selectivity but suffered from rapid turnover in human liver microsomes (HLM). Optimizing HLM stability proved challenging since it was not possible to identify a consistent site of metabolism and lowering lipophilicity proved unsuccessful. Key to overcoming this problem was the finding that introduction of a methyl group at the 6-position of the pyrido[3,4-d]pyrimidine core significantly improved HLM stability. Met ID studies suggested that the methyl group suppressed metabolism at the distant aniline portion of the molecule, likely by blocking the preferred pharmacophore through which P450 recognized the compound. This work ultimately led to the discovery of BOS172722 as a Phase 1 clinical candidate.	Sep 2018
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure of the epigenetic oncogene MMSET and inhibition by N-alkyl sinefungin derivatives Dominic Tisi , Elisabetta Chiarparin , Emiliano Tamanini , Puja Pathuri , Joseph E. Coyle , Adam Hold , Finn P. Holding , Nader Amin , Agnes C. L. Martin , Sharna J. Rich , Valerio Berdini , Jeff Yon , Paul Acklam , Rosemary Burke , Ludovic Drouin , Jenny E. Harmer , Fiona Jeganathan , Rob Van Montfort , Yvette Newbatt , Marcello Tortorici , Maura Westlake , Amy Wood , Swen Hoelder , Tom D. Heightman Acs Chemical Biology 11, 3093 - 3105 DOI: 10.1021/acschembio.6b00308 Show Abstract ▼ Abstract: The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.	Nov 2016
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	A fragment-based approach applied to a highly flexible target: Insights and challenges towards the inhibition of HSP70 isoforms Alan M. Jones , Isaac M. Westwood , James D. Osborne , Thomas P. Matthews , Matthew D. Cheeseman , Martin G. Rowlands , Fiona Jeganathan , Rosemary Burke , Diane Lee , Nadia Kadi , Manjuan Liu , Meirion Richards , Craig Mcandrew , Norhakim Yahya , Sarah Dobson , Keith Jones , Paul Workman , Ian Collins , Rob L. M. Van Montfort Scientific Reports 6 DOI: 10.1038/srep34701 Open Access Show Abstract ▼ Abstract: The heat shock protein 70s (HSP70s) are molecular chaperones implicated in many cancers and of significant interest as targets for novel cancer therapies. Several HSP70 inhibitors have been reported, but because the majority have poor physicochemical properties and for many the exact mode of action is poorly understood, more detailed mechanistic and structural insight into ligand-binding to HSP70s is urgently needed. Here we describe the first comprehensive fragment-based inhibitor exploration of an HSP70 enzyme, which yielded an amino-quinazoline fragment that was elaborated to a novel ATP binding site ligand with different physicochemical properties to known adenosine-based HSP70 inhibitors. Crystal structures of amino-quinazoline ligands bound to the different conformational states of the HSP70 nucleotide binding domain highlighted the challenges of a fragment-based approach when applied to this particular flexible enzyme class with an ATP-binding site that changes shape and size during its catalytic cycle. In these studies we showed that Ser275 is a key residue in the selective binding of ATP. Additionally, the structural data revealed a potential functional role for the ATP ribose moiety in priming the protein for the formation of the ATP-bound pre-hydrolysis complex by influencing the conformation of one of the phosphate binding loops.	Oct 2016
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	Exploiting protein conformational change to optimize adenosine-derived inhibitors of HSP70 Matthew D. Cheeseman , Isaac Westwood , Olivier Barbeau , Martin Rowlands , Sarah Dobson , Alan M. Jones , Fiona Jeganathan , Rosemary Burke , Nadia Kadi , Paul Workman , Ian Collins , Rob Van Montfort , Keith Jones Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5b02001 Open Access Show Abstract ▼ Abstract: HSP70 is a molecular chaperone and a key component of the heat-shock response. Because of its proposed importance in oncology, this protein has become a popular target for drug discovery, efforts which have as yet brought little success. This study demonstrates that adenosine-derived HSP70 inhibitors potentially bind to the protein with a novel mechanism of action, the stabilization by desolvation of an intramolecular salt-bridge which induces a conformational change in the protein, leading to high affinity ligands. We also demonstrate that through the application of this mechanism, adenosine-derived HSP70 inhibitors can be optimized in a rational manner.	May 2016
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Structure-based design of orally bioavailable 1H-pyrrolo[3,2-c]pyridine inhibitors of mitotic kinase monopolar spindle 1 (MPS1) Sébastien Naud , Isaac M. Westwood , Amir Faisal , Peter Sheldrake , Vassilios Bavetsias , Butrus Atrash , Kwai-Ming J. Cheung , Manjuan Liu , Angela Hayes , Jessica Schmitt , Amy Wood , Vanessa Choi , Kathy Boxall , Grace Mak , Mark Gurden , Melanie Valenti , Alexis De Haven Brandon , Alan Henley , Ross Baker , Craig Mcandrew , Berry Matijssen , Rosemary Burke , Swen Hoelder , Suzanne A. Eccles , Florence I. Raynaud , Spiros Linardopoulos , Rob L. M. Van Montfort , Julian Blagg Journal Of Medicinal Chemistry 56 (24), 10045 - 10065 DOI: 10.1021/jm401395s PMID: 24256217 Diamond Proposal Number(s): [8015] Open Access Show Abstract ▼ Abstract: The protein kinase MPS1 is a crucial component of the spindle assembly checkpoint signal and is aberrantly overexpressed in many human cancers. MPS1 is one of the top 25 genes overexpressed in tumors with chromosomal instability and aneuploidy. PTEN-deficient breast tumor cells are particularly dependent upon MPS1 for their survival, making it a target of significant interest in oncology. We report the discovery and optimization of potent and selective MPS1 inhibitors based on the 1H-pyrrolo[3,2-c]pyridine scaffold, guided by structure-based design and cellular characterization of MPS1 inhibition, leading to 65 (CCT251455). This potent and selective chemical tool stabilizes an inactive conformation of MPS1 with the activation loop ordered in a manner incompatible with ATP and substrate-peptide binding; it displays a favorable oral pharmacokinetic profile, shows dose-dependent inhibition of MPS1 in an HCT116 human tumor xenograft model, and is an attractive tool compound to elucidate further the therapeutic potential of MPS1 inhibition.	Dec 2013
I02-Macromolecular Crystallography	The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design Sylvain Couty , Isaac Westwood , Andrew Kalusa , Celine Cano , Jon Travers , Kathy Boxall , Chiau Ling Chow , Sam Burns , Jessica Schmitt , Lisa Pickard , Caterina Barillari , P. Craig Mcandrew , Paul A. Clarke , Spiros Linardopoulos , Roger J. Griffin , G. Wynne Aherne , Florence I. Raynaud , Paul Workman , Keith Jones , Rob Van Montfort Oncotarget 4, 1647 - 1661 DOI: 10.18632/oncotarget.1255 Open Access Show Abstract ▼ Abstract: The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.	Oct 2013

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