Recent Publications

Scroll down for patent applications, selected poster presentations and public-domain bioinformatics packages from the team.

Publications from the team:

Specific killing of DNA damage-response deficient cells with inhibitors of poly(ADP-ribose) glycohydrolase.
Gravells, P, Grant, E, Smith, KM, James, DI, Bryant, HE. DNA Repair, 2017, in press. doi: 10.1016/j.dnarep.2017.02.010

Discovery and Optimization of Allosteric Inhibitors of Mutant Isocitrate Dehydrogenase 1 (R132H IDH1) Displaying Activity in Human Acute Myeloid Leukemia Cells.
Jones, S, Ahmet, J, Ayton, K, Ball, M, Cockerill, M, Fairweather, E, Hamilton, N, Harper, P, Hitchin, J, Jordan, A, Levy, C, Lopez, R, McKenzie, E, Packer, M, Plant, D, Simpson, I, Simpson, P, Sinclair, I, Somervaille, TCP, Small, H, Spencer, GJ, Thomson, G, Tonge, M, Waddell, I, Walsh, J, Waszkowycz, B, Ogilvie, DJ. Journal of Medicinal Chemistry, 2016:59:11120. doi: 10.1021/acs.jmedchem.6b01320

First-in-class chemical probes against poly(ADP-ribose) glycohydrolase (PARG) inhibit DNA repair with differential pharmacology to olaparib.
James, DI, Smith KM, Jordan, AM, Fairweather, EF, Griffiths, LA, Hamilton, NS, Hitchin, JR, Hutton, CP, Jones, S, Kelly, P, McGonagle, AE, Small, H, Stowell, AIJ, Tucker, J, Waddell, ID, Waszkowycz, B, Ogilvie, DJ. ACS Chemical Biology, 2016:11:3179. doi: 10.1021/acschembio.6b00609

Discovery of potent inhibitors of the lysophospholipase autotaxin.
Shah, P, Cheasty, A, Foxton, F, Raynham, T, Farooq, M, Gutierrez, IF, Lejeune, A, Pritchard, M, Turnbull, A, Pang, L, Owen, P, Boyd, S, Stowell, A, Jordan, A, Hamilton, NM, Hitchin, JR, Stockley, M, Macdonald, E, Quesada, MJ, Trivier, E, Skeet, J, Ovaa, H, Moolenaar, WH, Ryder, H. Bioorganic and Medicinal Chemistry Letters, 2016:26:5403. doi: 10.1016/j.bmcl.2016.10.036

Mode of action of DNA-competitive small molecule inhibitors of tyrosyl DNA phosphodiesterase 2.
Hornyak, P, Askwith, T, Walker, S, Komulainen, E, Paradowski, M, Pennicott, LE, Bartlett, EJ, Brissett, NC, Raoof, A, Watson, M, Jordan, AM, Ogilvie, DJ, Ward, SE, Atack, JR, Pearl, LH, Caldecott, KW and Oliver, AW. Biochemical Journal, 2016:473:1869. doi: 10.1042/BCJ20160180

Identification of selective inhibitors of RET and comparison with current clinical candidates through development and validation of a robust screening cascade.
Watson, AJ, Hopkins, GV, Hitchin, S, Begum, H, Jones, S, Jordan, A, Holt, S, March, N, Newton, R, Small, H, Stowell, A, Waddell, ID, Waszkowycz, B and Ogilvie, DO. F1000Research, 2016:5:1005. doi: 10.12688/f1000research.8724.1

IncucyteDRC: An R package for the dose response analysis of live cell imaging data.
Chapman, PJ, James, DI, Watson, AJ, Hopkins, GV, Waddell, ID and Ogilvie, DO. F1000Research, 2016:5:962. doi: 10.12688/f1000research.8694.1

Anilinoquinazoline inhibitors of the RET kinase domain - elaboration of the 7-position.
Jordan, AM, Begum, H, Fairweather, E, Fritzl, S, Goldberg, K, Hopkins, GV, Hamilton, NM, Lyons, AJ, March, HN, Newton, R, Small, HF, Vishwanath, S, Waddell, ID, Waszkowycz, B and Ogilvie, DJ. Bioorganic and Medicinal Chemistry Letters, 2016:26:2724 doi: 10.1016/j.bmcl.2016.03.100

An HTS-compatible HTRF assay measuring the glycohydrolase activity of human PARG.
Stowell, A, James, DI, Waddell, ID, Bennett, N, Truman, C, Hardern, IM and Ogilvie, DJ. Analytical Biochemistry, 2016:503:58. doi: 10.1016/j.ab.2016.03.016

An assay to measure poly(ADP ribose) glycohydrolase (PARG) activity in cells.
James, D, Durant, S, Eckersley, K, Fairweather, E, Griffiths, L, Hamilton, N, Kelly, P, O'Connor, M, Shea, K, Waddell, ID, Ogilvie, DJ. F1000Research, 2016:5:736. doi: 10.12688/f1000research.8463.1

The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors.
Newton, R, Bowler, KA, Burns, EM, Chapman, PJ, Fairweather, EE, Fritzl, SJR, Goldberg, KM, Hamilton, NM, Holt, SV, Hopkins, GV, Jones, SD, Jordan, AM, Lyons, AJ, March N, McDonald, NQ, Maguire, LA, Mould, DP, Purkiss, AG, Small, HF, Stowell, AIJ, Thomson, GJ, Waddell, ID, Waszkowycz, B, Watson, AJ and Ogilvie, DJ. European Journal of Medicinal Chemistry, 2016:112:20-32 doi: 10.1016/j.ejmech.2016.01.039

Re-thinking "Academic" Drug Discovery – The Manchester Institute Perspective.
Jordan, AM, Waddell, ID and Ogilvie, DJ. Drug Discovery Today. 2015:20:525-35 doi: 10.1016/j.drudis.2014.12.011

Reversible Inhibitors of LSD1 as Therapeutic Agents in Acute Myeloid Leukemia: Clinical Significance and Progress to Date.
Mould, DP, McGonagle, AE, Wiseman, DH, Williams, EL and Jordan, AM. Medicinal Research Reviews 2015:35:586-618 doi: 10.1002/med.21334/

Elevated plasma 2-hydroxyglutarate levels after chemotherapy predict relapse in IDH1 and IDH2 mutated acute myeloid leukemia.
Wiseman, DH, Small, HF, Wilks, DP, Waddell, ID, Dennis, MW, Ogilvie , DJ and Somervaille TCP. British J of Heamotology 2014:166(1):145-8. doi: 10.1111/bjh.12826

Fragment-Based Hit Identification - Thinking in 3D.
Morley AD, Wyatt PG, Gilbert I, Bower J, Pugliese A, Merritt A, Chapman T, Birchall K, Mille D, Brennan P, Hoelder S, Brown N, Swarbrick M, Jordan A, Ley, SV. Drug Discovery Today. 2013:18:1221 doi: 10.1016/j.drudis.2013.07.011

Development and Evaluation of Selective, Reversible LSD1 Inhibitors Derived from Fragments.
Hitchin JR, Blagg J, Burke R, Cockerill M, Fairweather E, Hutton C, Jordan A, McAndrew C, Mould D, Mirza A, Thomson G, Wadell I, Ogilvie D. Medicinal Chemistry Communications. 2013:4:1513. doi: 10.1039/c3md00226h

Up-regulation of CD86 as a surrogate cellular biomarker for pharmacological inhibition of the histone demethylase LSD1.
Lynch JT, Cockerill M, Hitchin J, Somervaille TCP. Analytical Biochemistry. 2013:442:104 doi: 10.1016/j/ab/2013.07.032

Toxoflavins and deazaflavins as the first reported selective small molecule inhibitors of tyrosyl-DNA phosphodiesterase II.
Raoof A, Depledge P, Hamilton NM, Hamilton NS, Hitchin JR, Hopkins GV, Jordan AM, Maguire LA, McGonagle AM, Mould DP, Rushbrooke M, Small HF, Smith KM, Thomson GT, Turlais F, Waddell ID, Waskowycz B, Watson AJ, Ogilvie DO. Journal of Medicinal Chemistry. 2013:53:6352 doi: 10.1021/jm400568p

A fluorescence based assay for the AP-site cleavage activity of human tyrosyl DNA phosphodiesterase 1.
Thomson GT, Hamilton NS, Hopkins GV, Waddell ID, Watson AJ, Ogilvie DO. Analytical Biochemistry. 2013:440:1. doi: 10.1016/j.ab.2013.05.003

Generation of assays and antibodies to facilitate the study of human 5'-tyrosyl DNA phosphodiesterase.
Thomson G, Watson A, Caldecott K, Denneny O, Depledge P, Hamilton N, Hopkins G, Jordan A, Morrow C, Raoof A, Waddell I, Ogilvie D. Analytical Biochemistry. 2013:436:145. doi: 10.1016/j.ab.2013.02.001

The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells.
Harris WJ, Huang X, Lynch JT, Spencer GJ, Hitchin JR, Li Y, Ciceri F, Blaser JG, Greystoke BF, Jordan AM, Miller CJ, Ogilvie DJ, Somervaille TC. Cancer Cell. 2012:21(4):451 doi: 10.1016/j.ccr.2012.03.014

Novel Steroid Inhibitors of Glucose-6-Phosphate Dehydrogenase.
Hamilton NM, Dawson M, Fairweather E, Hamilton NS, Hitchin JR, James DI, Jones SD, Jordan AM, Lyons AJ, Small HF, Thomson GJ, Waddell ID, Ogilvie DJ. Journal of Medicinal Chemistry. 2012:55:4431. doi: 10.1021/jm300317k

A Novel Scalable and Stereospecific Synthesis of 3a- & 3β-amino-5 α -androstan-17-ones and 3 α - & 3β-amino-5 α -pregnan-20-ones.
Hitchin JR, Hamilton NM, Jordan AM, Lyons AJ, Ogilvie DJ. Tetrahedron Letters. 2012:53:2868 doi: 10.1016/j.tetlet.2012.03.124

The Medicinal Chemist’s Toolbox: An analysis of reactions used in the pursuit of drug candidates.
Roughley SD, Jordan AM. Journal of Medicinal Chemistry. 2011:54:3451 doi: 10.1021/jm200187y

Publications from our Collaborators:

Robotic Mammosphere Assay for High-Throughput Screening in Triple-Negative Breast Cancer
Fitzpatrick, PA, Akrap, N, Söderberg, EMV, Harrison, H, Thomson, GJ, Landberg, G. SLAS Discovery. 2017. In press. doi: 10.1177/2472555217692321

Elevated hypothalamic glucocorticoid levels are associated with obesity and hyperphagia in male mice.
Sefton, C, Harno, E, Davies, A, Small, H, Allen, T-J, Wray, JR, Lawrence, CB, Coll, AP, White, A. Endocrinology. 2016:157:4257 doi: 10.1210/en.2016-1571

Binding Mode and Selectivity of Steroids towards Glucose-6-phosphate Dehydrogenase from the Pathogen Trypanosoma cruzi.
Ortiz, C, Moraca, F, Mediros, A, Botta, M, Namilton, N and Comin, MA. Molecules 2016:21:368. doi: 10.3390/molecules21030368

The Extracellular-Regulated Protein Kinase 5 (ERK5) is a Key Regulator of Inflammation-Driven Cancer.
Finegan, KG, Perez-Madrigal, D, Hitchin, JR, Davies, C, Jordan, AM and Tournier, C. Cancer Research 2015:75:742-53 doi: 10.1158/0008-5472.CAN-13-3043

Torin1 mediated TOR Kinase inhibition reduces Wee1 levels and advances mitotic commitment in fission yeast and HeLa cells.
Atkin, J, Ferguson, J, Hitchin, J, Lichawska-Cieslar, A, Jordan, A, Pines, J, Wellbrock, C and Petersen, J. Journal of Cell Science 2014:127:1346 doi: 10.1242/jcs.146373

Discrepancies in Cancer Genomic Sequencing Highlight Opportunities for Driver Mutation Discovery.
Hudson, AM, Yates, T, Li, Y, Trotter, EW, Fawdar, S, Chapman, P, Lorigan, P, Biankin, AV, Miller, C and Brognard, J. Cancer Research 2014:74:6390 doi: 10.1158/0008-5472.CAN-14-1020

Topographical study of O6-alkylguanine DNA alkyltransferase repair activity and N7-methylguanine levels in resected lung tissue.
Crosbie, P, Harrison, K, Shah, R, Watson, A, Agius, R, Barber, P, Margison, G, and Povey, P. Chemico-Biological Interactions 2013:204:98 doi: 10.1016/j.cbi.2013.04.013

Repair and removal of azoxymethane-induced O6-methylguanine in rat colon by O6-methylguanine DNA methyltransferase and apoptosis.
Nyskohus, L, Watson, A, Margison, G, Le Leu, R, Kim, S, Lockette, T, Head, R, Young G, and Hu, Y. Mutation Research 2013:758:80 doi: 10.1016/j.mrgentox.2013.10.001

Protein Kinase C d deficiency causes Mendelian Systemic Lupus Erythematosus with B-cell Defective Apoptosis and Hyperproliferation.
Belot A, Kasher PR, Trotter EW, Fora A-P, DeBaud A-L, Rice GI, Szynkiewicz M, Zabot M-T, Rouvert I, Bhaskar S, Daly SB, Dickerson JE, Mayer J, O'Sullivan J, Juillard L, Urquhart JE, Fawdar S, Marusiak AA, Stephenson N, Waskowycz B, Beresford MW, Biesecker LG, Black GCM, Rene C, Fabien J-FN, Ranchin B, Cochat P, Gaffney PM, Rozenberg F, Lebon P, Malcus C, Crow YJ, Brognard J, Bonnefoy, N. Arthritis & Rheumatism. 2013:65:2161. doi: 10.1002/art.38008

Targeted Genetic Dependency Screen Facilitates Identification of Actionable Mutations in FGFR4, MAP3K9, and PAK5 in Lung Cancer.
Fawdar S, Trotter EW, Li Y, Stephenson NL, Hanke F, Marusiak AA, Edwards ZC, Ientile S, Waszkowycz B, Miller CJ, Brognard J. Proceeedings of the National Academy of Sciences. 2013:110:12426. doi: 10.1073/pnas.1305207110

Patent Applications:

"Autotaxin Inhibitory Compounds", Martin Lee Stockley, Ellen Catherine Macdonald, Pritom Shah, Allan Jordan, James Hitchin, Niall Hamilton, PCT Int. Appl. WO2016124939, 11th August 2016

"PARG Inhibitory Compounds", Alison E. McGonagle, Allan Jordan, Bohdan Waszkowycz, Colin Hutton, Ian Waddell, James R. Hitchin, Kate M. Smith, Niall M. Hamilton, PCT Int. Appl. WO2016097749, 23rd June 2016

"2,4-Dioxo-Quinazoline-6-Sulphonamide Derivatives as Inhibitors of PARG", Alison E. McGonagle, Allan M. Jordan, Bohdan Waszkowycz, Colin P. Hutton, Ian D. Waddell, James R. Hitchin, Kate M. Smith, Niall M. Hamilton, PCT Int. Appl. WO2016092326, 16th June 2016

"Quinazoline Compounds", Kristin Goldberg, Niall Hamilton, Stuart Jones, Allan Jordan, Amanda Lyons, Rebecca Newton, Donald Ogilvie, Bohdan Waszkowycz, PCT Int. Appl. WO2015079251, 4th June 2015

Selected Poster Presentations:

" Discovery and optimisation of benzimidazolone sulphonamides as potent, selective and cell-active inhibitors of poly(ADP Ribose) glycohydrolase (PARG), through high-throughput screening and computational approaches." AACR Annual Meeting, April 2016, New Orleans, LA

" Optimisation of quinazolinedione sulphonamides as novel inhibitors of poly(ADP ribose) glycohydrolase (PARG)." AACR Annual Meeting, April 2016, New Orleans, LA

" Inhibition of SMARCA2: a novel target for SMARCA4-deficient lung adenocarcinoma." AACR Annual Meeting, April 2015, Philadelphia, PA

" PARG inhibition: development of novel compounds and a biomarker strategy to determine cell line sensitivity in breast cancer." AACR Annual Meeting, April 2015, Philadelphia, PA

" The identification and structure-guided optimisation of potent and selective inhibitors of oncogenes in medullary thyroid carcinoma and lung adenocarcinoma." AACR Annual Meeting, April 2015, Philadelphia, PA

" Poly(ADP-ribose) glycohydrolase (PARG) inhibitors increase nuclear poly(ADP-ribose) after methylating DNA damage." EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics, November 2014, Barcelona, Spain

"Pharmacological characterisation of cell-active inhibitors of Poly(ADP-ribose) glycohydrolase (PARG)." AACR Annual Meeting, April 2014, San Diego, CA

"Development and Evaluation of Selective, Reversible LSD1 Inhibitors from Fragment Start Points." AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics, October 2013, Boston, MA

"Automation of in vitro HTRF assays on the Labcyte Access Workstation platform." ELRIG Drug Discovery, September 2013, Manchester, UK

"The discovery and optimisation of selective small-molecule inhibitors of human 5’-tyrosyl DNA phosphodiesterase 2 (Tdp2)." AACR Annual Meeting, April 2013, Washington DC

"Novel, cellular active inhibitors of G6PD, a key mediator of ROS-induced stress." AACR Annual Meeting, April 2012, Chicago, IL


Bio-informatics Package Repository:

Tidy methods for multiassay bioconductor objects

This package contains methods for converting bioconductor objects into tidy data frames, specifically PharmacoSet objects from the PharmacoGx package and MultiAssayExperiment objects from the MultiAssayExperiment package.

Link: Muli-Tidy Assay Package


Collateral Vulnerability Package.

This package contains code to run the CRUK Manchester Institute Drug Discovery Unit Collateral Vulnerability workflow.

Link: CV Package


IncucyteDRC

Package to import data generated by the Incucyte Zoom from Essen Biosciences and use this to fit dose response curves using the DRC package.

Link: Incucyte DRC