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11 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)	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
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Novel quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure–activity relationship, structural characterization, kinase profiling, and cellular proof of concept Liam Hudson , James Mui , Santiago Vázquez , Diana M. Carvalho , Eleanor Williams , Chris Jones , Alex N. Bullock , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00782 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: Structure–activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.	Aug 2018
I04-Macromolecular Crystallography	Structure Enabled Discovery of a Stapled Peptide Inhibitor to Target the Oncogenic Transcriptional Repressor TLE1 Sally Mcgrath , Marcello Tortorici , Ludovic Drouin , Savade Solanki , Lewis Vidler , Isaac Westwood , Peter Gimeson , Rob Van Montfort , Swen Hoelder Chemistry - A European Journal DOI: 10.1002/chem.201700747 Diamond Proposal Number(s): [14891, 6385, 8015, 10088] Show Abstract ▼ Abstract: TLE1 is an oncogenic transcriptional co-repressor that exerts its repressive effects through binding of transcription factors. Inhibition of this protein-protein interaction represents a putative cancer target but no small molecule inhibitors have been published for this challenging interface. In this manuscript, we report the structure enabled design and synthesis of a constrained peptide inhibitor of TLE1. Our design featured introduction of a four carbon atom linker into the peptide epitope found in many TLE1 binding partners. We developed a concise synthetic route to a proof of concept peptide cycFWRPW. Biophysical testing by ITC and thermal shift assays showed that whilst the constrained peptide bound potently, it had an approximately five fold higher Kd than the unconstrained peptide. Our co-crystal structure suggested that the reduced affinity is likely due to a small shift of one side-chain compared to the otherwise well conserved conformation of the acyclic peptide. Our work describes a constrained peptide inhibitor that may serve as the basis for improved inhibitors.	Mar 2017
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
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Rapid Discovery of Pyrido[3,4- d ]pyrimidine Inhibitors of Monopolar Spindle Kinase 1 (MPS1) Using a Structure-Based Hybridization Approach Paolo Innocenti , Hannah L. Woodward , Savade Solanki , Sébastien Naud , Isaac Westwood , Nora Cronin , Angela Hayes , Jennie Roberts , Alan T. Henley , Ross Baker , Amir Faisal , Grace Wing-yan Mak , Gary Box , Melanie Valenti , Alexis De Haven Brandon , Lisa O’ Fee , Harry Saville , Jessica Schmitt , Berry Matijssen , Rosemary Burke , Rob Van Montfort , Florence I. Raynaud , Suzanne A. Eccles , Spiros Linardopoulos , Julian Blagg , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.5b01811 Show Abstract ▼ Abstract: Monopolar spindle 1 (MPS1) plays a central role in the transition of cells from metaphase to anaphase and is one of the main components of the spindle assembly checkpoint. Chromosomally unstable cancer cells rely heavily on MPS1 to cope with the stress arising from abnormal numbers of chromosomes and centrosomes and are thus more sensitive to MPS1 inhibition than normal cells. We report the discovery and optimization of a series of new pyrido[3,4-d]pyrimidine based inhibitors via a structure-based hybridization approach from our previously reported inhibitor CCT251455 and a modestly potent screening hit. Compounds in this novel series display excellent potency and selectivity for MPS1, which translates into biomarker modulation in an in vivo human tumor xenograft model.	Apr 2016
I02-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Naturally Occurring Mutations in the MPS1 Gene Predispose Cells to Kinase Inhibitor Drug Resistance M. D. Gurden , Isaac Westwood , A. Faisal , S. Naud , K. M. J. Cheung , C. Mcandrew , A. Wood , J. Schmitt , K. Boxall , G. Mak , P. Workman , R. Burke , S. Hoelder , J. Blagg , Rob Van Montfort , S. Linardopoulos Cancer Research 75 (16), 3340 - 3354 DOI: 10.1158/0008-5472.CAN-14-3272 PMID: 26202014 Diamond Proposal Number(s): [8015, 10088] Show Abstract ▼ Abstract: Acquired resistance to therapy is perhaps the greatest challenge to effective clinical management of cancer. With several inhibitors of the mitotic checkpoint kinase MPS1 in preclinical development, we sought to investigate how resistance against these inhibitors may arise so that mitigation or bypass strategies could be addressed as early as possible. Toward this end, we modeled acquired resistance to the MPS1 inhibitors AZ3146, NMS-P715, and CCT251455, identifying five point mutations in the kinase domain of MPS1 that confer resistance against multiple inhibitors. Structural studies showed how the MPS1 mutants conferred resistance by causing steric hindrance to inhibitor binding. Notably, we show that these mutations occur in nontreated cancer cell lines and primary tumor specimens, and that they also preexist in normal lymphoblast and breast tissues. In a parallel piece of work, we also show that the EGFR p.T790M mutation, the most common mutation conferring resistance to the EGFR inhibitor gefitinib, also preexists in cancer cells and normal tissue. Our results therefore suggest that mutations conferring resistance to targeted therapy occur naturally in normal and malignant cells and these mutations do not arise as a result of the increased mutagenic plasticity of cancer cells.	Aug 2015
I02-Macromolecular Crystallography I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Fragment-Based Screening Maps Inhibitor Interactions in the ATP-Binding Site of Checkpoint Kinase 2 Cris Silva-santisteban , Isaac Westwood , Kathy Boxall , Nathan Brown , Sam Peacock , Craig Mcandrews , Elaine Barrie , Meirion Richards , Amin Mirza , Antony W. Oliver , Rosemary Burke , Swen Hoelder , Keith Jones , G. Wynne Aherne , Julian Blagg , Ian Collins , Michelle D. Garrett , Rob L.m. Van Montfort , Qiming Jane Wang Plos One 8 (6) DOI: 10.1371/journal.pone.0065689 PMID: 23776527 Open Access Show Abstract ▼ Abstract: Checkpoint kinase 2 (CHK2) is an important serine/threonine kinase in the cellular response to DNA damage. A fragmentbased screening campaign using a combination of a high-concentration AlphaScreenTM kinase assay and a biophysical thermal shift assay, followed by X-ray crystallography, identified a number of chemically different ligand-efficient CHK2 hinge-binding scaffolds that have not been exploited in known CHK2 inhibitors. In addition, it showed that the use of these orthogonal techniques allowed efficient discrimination between genuine hit matter and false positives from each individual assay technology. Furthermore, the CHK2 crystal structures with a quinoxaline-based fragment and its follow-up compound highlight a hydrophobic area above the hinge region not previously explored in rat	Jun 2013
I24-Microfocus Macromolecular Crystallography	Design of potent and selective hybrid inhibitors of the mitotic kinase Nek2: SAR, structural biology and cellular activity Richard Bayliss , Swen Hoelder , Paulo Innocent , K-m. Cheung , S. Solanki , C Mas-droux , Fiona Rowan , S. Yeoh , K. Boxall , M. Westlake , L. Pickard , T Hardy , Joanne Baxter , G. W. Aherne , A. Fry Journal Of Medicinal Chemistry 55 (7), 3228-41 DOI: 10.1021/jm201683b PMID: 22404346 Diamond Proposal Number(s): [6388] Show Abstract ▼ Abstract: We report herein a series of Nek2 inhibitors based on an aminopyridine scaffold. These compounds have been designed by combining key elements of two previously discovered chemical series. Structure based design led to aminopyridine (R)-21, a potent and selective inhibitor able to modulate Nek2 activity in cells.	Apr 2012
I03-Macromolecular Crystallography	Benzimidazole Inhibitors Induce a DFG-Out Conformation of Never in Mitosis Gene A-Related Kinase 2 (Nek2) without Binding to the Back Pocket and Reveal a Nonlinear Structure−Activity Relationship Savade Solanki , Paolo Innocenti , Corine Mas-droux , Kathy Boxall , Caterina Barillari , Rob L. M. Van Montfort , G. Wynne Aherne , Richard Bayliss , Swen Hoelder Journal Of Medicinal Chemistry 54 (6), 1626 - 1639 DOI: 10.1021/jm1011726 PMID: 21366329 Show Abstract ▼ Abstract: We describe herein the structure−activity relationship (SAR) and cocrystal structures of a series of Nek2 inhibitors derived from the published polo-like kinase 1 (Plk1) inhibitor (R)-1. Our studies reveal a nonlinear SAR for Nek2 and our cocrystal structures show that compounds in this series bind to a DFG-out conformation of Nek2 without extending into the enlarged back pocket commonly found in this conformation. These observations were further investigated, and structure-based design led to Nek2 inhibitors derived from (R)-1 with more than a hundred-fold selectivity against Plk1.	Mar 2011
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Aminopyrazine Inhibitors Binding to an Unusual Inactive Conformation of the Mitotic Kinase Nek2: SAR and Structural Characterization Daniel K. Whelligan , Savade Solanki , Dawn Taylor , Douglas W. Thomson , Kwai-ming J. Cheung , Kathy Boxall , Corine Mas-droux , Caterina Barillari , Samantha Burns , Charles G. Grummitt , Ian Collins , Rob L. M. Van Montfort , G. Wynne Aherne , Richard Bayliss , Swen Hoelder Journal Of Medicinal Chemistry 53 (21), 7682 - 7698 DOI: 10.1021/jm1008727 PMID: 20936789 Open Access Show Abstract ▼ Abstract: We report herein the first systematic exploration of inhibitors of the mitotic kinase Nek2. Starting from HTS hit aminopyrazine 2, compounds with improved activity were identified using structure-based design. Our structural biology investigations reveal two notable observations. First, 2 and related compounds bind to an unusual, inactive conformation of the kinase which to the best of our knowledge has not been reported for other types of kinase inhibitors. Second, a phenylalanine residue at the center of the ATP pocket strongly affects the ability of the inhibitor to bind to the protein. The implications of these observations are discussed, and the work described here defines key features for potent and selective Nek2 inhibition, which will aid the identification of more advanced inhibitors of Nek2.	Nov 2010

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