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Discovery Technology – Publications
2015
- Issa et al.. “Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study..” Lancet Oncology 16, no. 9 2015 Sep : 1099-110. DOI: 10.1016/S1470-2045(15)00038-8.
- Murray et al.. “Fragment-Based Discovery of Potent and Selective DDR1/2 Inhibitors.” ACS Med. Chem. Lett. 4 June 2015
- Ludlow et al.. “Detection of Secondary Binding sites in Proteins using Fragment Screening.” PNAS, 11 December 2015 (www.pnas.org/cgi/doi/10.1073/pnas.1518946112)
- Day et al.. “The Synthesis of 3,3-Dimethyl Aza- and Diazaindolines Using a Palladium-Catalysed Intramolecular Reductive Cyclisation.” Thieme. 2015. DOI: 10.1055/s-0035-1560320
- Chessari et al.. “Fragment-Based Drug Discovery Targeting Inhibitor of Apoptosis Proteins: Discovery of a Non-Alanine Lead Series with Dual Activity Against cIAP1 and XIAP.” Journal of Medical Chemistry. 28 July 2015. DOI: 10.1021/acs.jmedchem.5b00706 .
- Amin et al.. “1H, 15N and 13C backbone assignments of GDP-bound human H-Ras mutant G12V.” Springer Link. 15 September 2015. DOI: 10.1007/s12104-015-9649-4
- Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783
- Murray et al.. “Opportunity Knocks: Organic Chemistry for Fragment-Based Drug Discovery (FBDD).” Angewandte Chemie. 3 November 2015. DOI: 10.1002/anie.201506783 .
2014
- Fang et al.. “: The Novel, Small-Molecule DNA Methylation Inhibitor SGI-110 as an Ovarian Cancer Chemosensitizer.” Clin Cancer Res; 20(24) December 15, 2014
- Smyth et al.. “Inhibition of HSP90 by AT13387 Delays the Emergence of Resistance to BRAF Inhibitors and Overcomes Resistance to Dual BRAF and MEK Inhibition in Melanoma Models.” Mol Cancer Ther 2014;13:2793-2804.
- Chen et al. “A Phase 1 Study of cyclin-dependent kinase inhibitor, AT7519, in patients with advanced cancer: NCIC Clinical Trials Group IND 177.” Br. J. Cancer 2014 Dec 9; 111(12):2262-7
- Johnson et al. “Structure-Based Design of Type II Inhibitors Applied to Maternal Embryonic Leucine Zipper Kinase.” ACS Medicinal Chemistry Letters, DOI: 10.1021/ml5001273
- Hopkins et al. “The role of ligand efficiency metrics in drug discovery.” Nature Reviews Drug Discovery vol.13 (2014): 105-121. DOI: 10.1038/nrd4163
- Saxty et al. “Identification of orally bioavailable small-molecule inhibitors of hematopoietic prostaglandin D2 synthase using X-ray fragment based drug discovery.” Med. Chem. Commun. vol.5 (2014): 134-141. DOI: 10.1039/c3md00280b
- Shapiro et al.. “First-in-Human Phase I Dose Escalation Study of a Second-Generation Non-Ansamycin HSP90 Inhibitor, AT13387, in Patients with Advanced Solid Tumors.” Clinical Cancer Research. 21 October 2014. DOI: 10.1158/1078-0432.CCR-14-0979
- Saalau-Bethell et al.. “Crystal Structure of Human Soluble Adenylate Cyclase Reveals a Distinct, Highly Flexible Allosteric Bicarbonate Binding Pocket.” ChemMedChem, 24 February 2014. DOI: 10.1002/cmdc.201300480
- Hall et al.. “Efficient exploration of chemical space by fragment-based screening.” Science Direct. 28 September 2014. DOI: 10.1016/j.pbiomolbio.2014.09.007
- Cleasby et al.. “Structure of the BTB Domain of Keap1 and Its Interaction with the Triterpenoid Antagonist CDDO.” PLOS | ONE. 4 June 2014. DOI: 10.1371/journal.pone.0098896
- Johnson et al. “Fragment-Based Discovery of Type I Inhibitors of Maternal Embryonic Leucine Zipper Kinase.” ACS Medicinal Chemistry Letters, DOI:10.1021/ml5001245
2013
- Howard et al. “Fragment-Based Discovery of 6-Azaindazoles As Inhibitors of Bacterial DNA Ligase.” ACS Medicinal Chemistry Letters (2013). DOI: 10.1021/ml4003277 .
- Jhoti et al.. “The ‘rule of three’ for fragment-based drug discovery: where are we now?.” Nature Reviews Drug Discovery (2013). DOI: DOI:10.1038/nrd3926-c1 .
- Crawford et al.. “SAHA abrogates FLIP-mediated inhibition of SMAC mimetic-induced apoptosis in mesothelioma.” Cell Death Dis. 2013 Jul; 4(7): e733 .
2012
- Chaneton, et al. “Serine is a natural ligand and allosteric activator of pyruvate kinase M2.” Nature 2012. DOI: 10.1038/nature11540.
- Saalau-Bethell, et al. “Discovery of an allosteric mechanism for the regulation of HCV NS3 protein function.” Nature Chemical Biology 2012. DOI: 10.1038/NCHEMBIO.1081.
- Thomas G. Davies and Ian J. Tickle. “Fragment Screening Using X-Ray Crystallography.” Topics in Current Chemistry 317 2012: 33-59. DOI: 10.1007/128_2011_179.
- The HSP90 Inhibitor, AT13387, is Effective Against Imatinib-Sensitve and -Resistant Gastrointestinal Stromal Tumours
- Experiences of Fragment-based Drug Discovery
2011
- Alessandri et al. “Induction of Eosinophil Apoptosis by the Cyclin-Dependent Kinase Inhibitor AT7519 Promotes the Resolution of Eosinophil-Dominant Allergic Inflammation.” PLoS ONE 6, no. 9 2011: e25683. DOI: 10.1371/journal.pone.0025683.
- Arkenau et al. “A phase I dose escalation study of AT9283, a small molecule inhibitor of aurora kinases, in patients with advanced solid malignancies.” Annals of Oncology 2011. DOI: 10.1093/annonc/mdr451.
- Brito et al. “Comparative pre-clinical evaluation of receptor tyrosine kinase inhibitors for the treatment of multiple myeloma.” Leukemia Research 35, no. 9 2011: 1233-1240. DOI: 10.1016/j.leukres.2011.01.011.
- Heightman, Tom D. “Therapeutic prospects for epigenetic modulation.” Expert Opinion on Therapeutic Targets 15, no. 6 2011: 729-740. DOI: 10.1517/14728222.2011.561786.
- Mahadevan et al. “A phase I pharmacokinetic and pharmacodynamic study of AT7519, a cyclin-dependent kinase inhibitor in patients with refractory solid tumors.” Annals of Oncology 22, no. 9 2011: 2137-2143. DOI: 10.1093/annonc/mdq734.
- Paul N. Mortenson and Christopher W. Murray. “Assessing the lipophilicity of fragments and early hits.” Journal of Computer-Aided Molecular Design 25, no. 7 2011: 663-667. DOI: 10.1007/s10822-011-9435-z.
- Podesta et al. “Adaptation of the plasma inhibitory activity assay to detect Aurora, ABL and FLT3 kinase inhibition by AT9283 in pediatric leukemia.” Leukemia Research 35, no. 9 2011: 1273-1275. DOI: 10.1016/j.leukres.2011.05.022.
- Qi et al. “AT9283, a novel aurora kinase inhibitor suppresses tumor growth in aggressive B-cell lymphomas.” International Journal of Cancer 2011. DOI: 10.1002/ijc.26324.
- Santo et al. “Antimyeloma Activity of a Multitargeted Kinase Inhibitor, AT9283, via Potent Aurora Kinase and STAT3 Inhibition Either Alone or in Combination with Lenalidomide.” Clinical Cancer Research 17, no. 10 2011: 3259–71. DOI: 10.1158/1078-0432.CCR-10-3012.
- Squires et al. “Potent, selective inhibitors of Fibroblast Growth Factor Receptor define Fibroblast Growth Factor dependence in pre-clinical cancer models.” Molecular Cancer Therapeutics 10, no. 22 2011: 1542-1552. DOI: 10.1158/1535-7163.MCT-11-0426.
- Verdonk et al. “Docking performance of fragments and drug-like compounds.” Journal of Medicinal Chemistry 54, no. 15 2011: 5422–5431. DOI: 10.1021/jm200558u.
- Williams, Glyn. “The pyramid approach to fragment-based biophysical screening.” In Label-Free Technologies for Drug Discovery, edited by Matthew Cooper and Lorenz M. Mayr, 241-253. Chichester, UK: John Wiley & Sons Ltd 2011. ISBN: 978-0-470-74683-7.
- Yap et al. “Preclinical Pharmacology, Antitumor Activity, and Development of Pharmacodynamic Markers for the Novel, Potent AKT Inhibitor CCT128930.” Molecular Cancer Therapeutics 10, no. 2 2011: 360-71. DOI: 10.1158/1535-7163.MCT-10-0760.
2010
- Cho et al. “4-(Pyrazol-4-yl)-pyrimidines as Selective Inhibitors of Cyclin-Dependent Kinase 4/6.” Journal of Medicinal Chemistry 53, no. 22 2010: 7938–7957. DOI: 10.1021/jm100571n.
- Christopher W. Murray and Tom L. Blundell. “Structural Biology in Fragment-Based Drug Design.” Current Opinion in Structural Biology 20, no. 4 2010: 497-507. DOI: 10.1016/j.sbi.2010.04.003.
- Dawson M. A. et al. “AT9283, a potent inhibitor of the Aurora kinases and Jak2, has therapeutic potential in myeloproliferative disorders.” British Journal of Haematology 150, no. 1 2010: 46-57. DOI: 10.1111/j.1365-2141.2010.08175.x.
- McHardy et al. “Discovery of 4-Amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides As Selective, Orally Active Inhibitors of Protein Kinase B (Akt).” Journal of Medicinal Chemistry 53, no. 5 2010: 2239–2249. DOI: 10.1021/jm901788j.
- Murray et al. “Fragment-Based Drug Discovery Applied to HSP90. Discovery of Two Lead Series with High Ligand Efficiency.” Journal of Medicinal Chemistry 53, no. 16 2010: 5942–5955. DOI: 10.1021/jm100059d.
- Santo et al. “AT7519, A novel small molecule multi-cyclin-dependent kinase inhibitor, induces apoptosis in multiple myeloma via GSK-3beta activation and RNA polymerase II inhibition.” Oncogene 29, no. 16 2010: 2325-2336. DOI: 10.1038/onc.2009.510.
- Squires M. et al. “AT7519, a Cyclin-Dependent Kinase Inhibitor, Exerts Its Effects by Transcriptional Inhibition in Leukemia Cell Lines and Patient Samples.” Molecular Cancer Therapeutics 9, no. 4 2010: 920-928. DOI: 10.1158/1535-7163.MCT-09-1071.
- Tanaka et al. “Activity of the multi-targeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL positive leukemic cells.” Blood 116, no. 12 2010: 2089-2095. DOI: 10.1182/blood-2009-03-211466.
- Woodhead et al. “Discovery of (2,4-Dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a Novel Inhibitor of the Molecular Chaperone Hsp90 by Fragment Based Drug Design.” Journal of Medicinal Chemistry 53, no. 16 2010: 5956–5969. DOI: 10.1021/jm100060b.
2009
- Christopher W. Murray and David C. Rees. “The rise of fragment based drug discovery.” Nature Chemistry 1, no. 3 2009: 187-192. DOI: 10.1038/nchem.217.
- Curry J. et al. “Aurora kinase inhibition in mitosis: Strategies for optimising the use of aurora kinase inhibitors such as AT9283.” Cell Cycle 8, no. 12 2009: 1-9. DOI: 10.4161/cc.8.12.8741.
- Davies et al. “Fragment-Based Discovery of Inhibitors of Protein Kinase B.” Current Topics in Medicinal Chemistry 9, no. 18 2009: 1705-1717.
- Day et al. “Crystal structure of human CDK4 in complex with a D-type cyclin.” Proceedings of the National Academy of Sciences 106, no. 11 2009: 4166-4170. DOI: 10.1073/pnas.0809645106.
- Howard et al. “Fragment-Based Discovery of the Pyrazol-4-yl urea (AT9283), a Multi-targeted Kinase Inhibitor with Potent Aurora Kinase Activity.” Journal of Medicinal Chemistry 52, no. 2 2009: 379–388. DOI: 10.1021/jm800984v.
2008
- Frederickson et al. “Fragment-Based Discovery of Mexiletine Derivatives as Orally Bioavailable Inhibitors of Urokinase-Type Plasminogen Activator.” Journal of Medicinal Chemistry 51, no. 2 2008: 183–186. DOI: 10.1021/jm701359z.
- Marcel L. Verdonk and David C. Rees. “Group Efficiency: A Guideline for Hits-to-Leads Chemistry.” ChemMedChem 3, no. 8 2008: 1179–1180. DOI: 10.1002/cmdc.200800132.
- Miles Congreve et al. “Recent Developments in Fragment-Based Drug Discovery.” Journal of Medicinal Chemistry 51, no. 13 2008: 3661–3680. DOI: 10.1021/jm8000373.
- Paul G. Wyatt, Andrew J. Woodhead, Valerio Berdini et al. “Identification of N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), a Novel Cyclin Dependent Kinase Inhibitor Using Fragment-Based X-Ray Crystallography and Structure Based Drug Design.” Journal of Medicinal Chemistry 51, no. 16 2008: 4986–4999. DOI: 10.1021/jm800382h.
- Verdonk et al. “Protein−Ligand Docking against Non-Native Protein Conformers.” Journal of Chemical Information and Modeling 48, no. 11 2008: 2214–2225. DOI: 10.1021/ci8002254.
2007
- Christopher W. Murray et al. “Application of Fragment Screening by X-ray Crystallography to β-Secretase.” Journal of Medicinal Chemistry 50, no. 6 2007: 1116–1123. DOI: 10.1021/jm0611962.
- Jhoti, Harren; Leach, Andrew (Eds.). “Structure-based Drug Discovery.” Springer, XII, 252p., Hardcover 2007. ISBN: 978-1-4020-4406-9.
- Michael J. Hartshorn, et al. “Diverse, High-Quality Test Set for the Validation of Protein−Ligand Docking Performance.” Journal of Medicinal Chemistry 50, no. 4 2007: 726–741. DOI: 10.1021/jm061277y.
- Miles Congreve et al. “Application of Fragment Screening by X-ray Crystallography to the Discovery of Aminopyridines as Inhibitors of β-Secretase.” Journal of Medicinal Chemistry 50, no. 6 2007: 1124–1132. DOI: 10.1021/jm061197u.
- P. Day, et al. “Structure of a CBS-domain pair from the regulatory γ1 subunit of human AMPK in complex with AMP and ZMP.” Acta Crystallographica D63 2007: 587-596. DOI: 10.1107/S0907444907009110.
- Saxty et al. “Identification of Inhibitors of Protein Kinase B Using Fragment-Based Lead Discovery.” Journal of Medicinal Chemistry 50, no. 10 2007: 2293–2296. DOI: 10.1021/jm070091b.
2006
- Davies Thomas G., et al. “Pyramid: An integrated platform for fragment-based drug discovery.” Fragment-based approaches in drug discovery: Volume 34, Chapter 10, pp 193-214. Edited by W Jahnke and D. A. Erlanson. WILEY-VCG Verlag GmbH & Co. KGaA, Weinheim 2007. ISBN: 978-3-527-31291-7.
- Howard, N., et al. “Application of Fragment Screening and Fragment Linking to the Discovery of Novel Thrombin Inhibitors.” Journal of Medicinal Chemistry 49, no. 4 2006: 1346–1355. DOI: 10.1021/jm050850v.
- Mooij W. T. M. et al. “Automated Protein–Ligand Crystallography for Structure-Based Drug Design.” ChemMedChem 1, no. 8 2006: 827–838. DOI: 10.1002/cmdc.200600074.
- Murray C. W., Verdonk et al. “Entropic consequences of linking ligands.” Fragment-based approaches in drug discovery: Volume 34, Chapter 3, pp 55-66. Edited by W Jahnke and D. A. Erlanson. WILEY-VCG Verlag GmbH & Co. KGaA, Weinheim 2006. ISBN: 978-3-527-31291-7.
2005
- Gill, A., et al. “The Discovery of Novel Protein Kinase Inhibitors by Using Fragment-Based High-Throughput X-ray Crystallography.” ChemBioChem 6, no. 3 2005: 506–512. DOI: 10.1002/cbic.200400188.
- Gill, A.L., et al. “Identification of Novel p38α MAP Kinase Inhibitors Using Fragment-Based Lead Generation.” Journal of Medicinal Chemistry 48, no. 2 2005: 414–426. DOI: 10.1021/jm049575n.
- Hartshorn, M.J., et al. “Fragment-Based Lead Discovery Using X-ray Crystallography.” Journal of Medicinal Chemistry 48, no. 2 2005: 403–413. DOI: 10.1021/jm0495778.
- Kirton, S.B., et al. “Prediction of binding modes for ligands in the cytochromes P450 and other heme-containing proteins.” Proteins: Structure, Function, and Bioinformatics 58, no. 4 2005: 836–844. DOI: 10.1002/prot.20389.
- Miles Congreve, Christopher W. Murray and Tom L. Blundell. “Keynote review: Structural biology and drug discovery.” Drug Discovery Today 10, no. 13 2005: 895–907. DOI: 10.1016/S1359-6446(05)03484-7.
- Robin A.E. Carr, Miles Congreve, Christopher W. Murray, David C. Rees. “Fragment-based lead discovery: leads by design.” Drug Discovery Today 10, no. 14 2005: 987–992. DOI: 10.1016/S1359-6446(05)03511-7.
- Thompson N., Lyons J. “Recent progress in targeting the Raf/MEK/ERK pathway with inhibitors in cancer drug discovery.” Current Opinion in Pharmacology 5, no. 4 2005: 350–356. DOI: 10.1016/j.coph.2005.04.007.
2004
- Gill, A. L. “New Lead Generation Strategies for Protein Kinase Inhibitors – Fragment Based Screening Approaches.” Mini-Reviews in Medicinal Chemistry 4, no. 3 2004: 301-311.
- Patel, S., et al. “Apo and Inhibitor Complex Structures of BACE (β-secretase).” Journal of Molecular Biology 343, no. 2 2004: 407–416. DOI: 10.1016/j.jmb.2004.08.018.
- Rees, D.C., et al. “Fragment-based lead discovery.” Nature Reviews Drug Discovery 3 2004: 660-672. DOI: 10.1038/nrd1467.
- Tickle, I., et al. “High-throughput protein crystallography and drug discovery.” Chemical Society Reviews 33, no. 8 2004: 558-565. DOI: 10.1039/B314510G.
- Verdonk M. L., Hartshorn, M. J. “Structure-guided fragment screening for lead discovery.” Current Opinion in Drug Discovery and Development 7 2004: 404-410.
- Verdonk, M. L., et al. “Virtual Screening Using Protein−Ligand Docking: Avoiding Artificial Enrichment.” Journal of Chemical Information and Modeling 44, no. 3 2004: 793–806. DOI: 10.1021/ci034289q.
- Williams, P. A., et al. “Crystal Structures of Human Cytochrome P450 3A4 Bound to Metyrapone and Progesterone.” Science 305, no. 5684 2004: 683-686. DOI: 10.1126/science.1099736.
2003
- Birch, L., et al. “Sensitivity of molecular docking to induced fit effects in influenza virus neuraminidase.” Journal of Computer-Aided Molecular Design 16, no. 12 2003: 855-869. DOI: 10.1023/A:1023844626572.
- Congreve, M.S. et al. “Detection of Ligands from a Dynamic Combinatorial Library by X-ray Crystallography.” Angewandte Chemie International Edition 42, no. 37 2003: 4479–4482. DOI: 10.1002/anie.200351951.
- Congreve, M.S. et al. “A ‘Rule of Three’ for fragment-based lead discovery?.” Drug Discovery Today 8, no. 19 2003: 876–877. DOI: 10.1016/S1359-6446(03)02831-9.
- Frederickson M., Vuillard, L. et al. “Novel selenium containing non-detergent sulphobetaines.” Tetrahedron Letters 44, no. 43 2003: 7925–7928. DOI: 10.1016/j.tetlet.2003.09.004.
- Hartshorn, MJ. “AstexViewer™: a visualisation aid for structure-based drug design.” Journal of Computer-Aided Molecular Design 16, no. 12 2003: 871-881. DOI: 10.1023/A:1023813504011.
- Sharff A. , Jhoti, H. “High-throughput crystallography to enhance drug discovery.” Current Opinion in Chemical Biology 7, no. 3 2003: 340–345. DOI: 10.1016/S1367-5931(03)00062-0.
- van Montfort, R.L.M., et al. “Oxidation state of the active-site cysteine in protein tyrosine phosphatase 1B.” Nature 423 2003: 773-777. DOI: 10.1038/nature01681.
- Verdonk, M. L., et al. “Improved protein–ligand docking using GOLD.” Proteins: Structure, Function, and Bioinformatics 52, no. 4 2003: 609–623. DOI: 10.1002/prot.10465.
- Watson P. Verdonk, M. , Hartshorn M.J. “A web-based platform for virtual screening.” Journal of Molecular Graphics and Modelling 22, no. 1 2003: 71–82. DOI: 10.1016/S1093-3263(03)00137-2.
- Williams, P.A., et al. “Crystal structure of human cytochrome P450 2C9 with bound warfarin.” Nature 424, no. 6947 2003: 464-468. DOI: 10.1038/nature01862.
- Yon J., Jhoti, H. “High-throughput structural genomics and proteomics: where are we now?.” Targets 2, no. 5 2003: 201–207. DOI: 10.1016/S1477-3627(03)02348-1.
2002
- Blundell T.L., Jhoti, H. et al. “High-throughput crystallography for lead discovery in drug design.” Nature Reviews Drug Discovery 1 2002: 45-54. DOI: 10.1038/nrd706.
- Carr R., Hann, M. “The right road to drug discovery?.” Modern Drug Discovery 5, no. 4 2002: 45-48.
- Carr R., Jhoti, H. “Structure-based screening of low-affinity compounds.” Drug Discovery Today 7, no. 9 2002: 522–527. DOI: 10.1016/S1359-6446(02)02245-6.
- Murray C.W., Verdonk, M.L. “The consequences of translational and rotational entropy lost by small molecules on binding to proteins.” Journal of Computer-Aided Molecular Design 16, no. 10 2002: 741-753. DOI: 10.1023/A:1022446720849.