Department of Pharmacy and Pharmacology

michael_threadgill

Professor- Pharmacy & Pharmacology

5 West 3.9

Email:

Tel: +44 (0) 1225 38 6840  

 

Prof  Michael Threadgill 

Profile

The research focus of the Threadgill group is drug design and delivery. We work on the application of medicinal chemistry (structure-based drug design, chemical synthesis, biochemical and cell biological evaluation) to developing new cancer treatments. Where the biochemistry of other diseases is similar (haemorrhagic shock, stroke, myocardial infarction, etc.), our work has branched out into these areas. We also research new synthetic methods in organic heterocyclic chemistry. Collaborations in Bath, Aberystwyth, Finland, India and Poland are important to our work.

Current research

PARP inhibitors

The poly(ADP-ribose)polymerases (PARPs) are a family of enzymes which use ADP-ribose units from NAD+ to build poly(ADP-ribose) polymers on target proteins. PARP-1 regulates DNA repair and gene expression through NF-κB. We developed 5-AIQ as a leading inhibitor of PARP-1, potent in models of metastatic cancer, inflammation and ischaemia-reperfusion injury. We have designed some of the most isoform-selective inhibitors of PARP-2 reported to date. Currently, we use structure-based drug design to develop new potent inhibitors of the tankyrases (PARP-5a,5b) in a major project funded by AICR.

Tumour-selective delivery of drugs

In cancer chemotherapy, it is important that the cytotoxic drug acts selectively in the tumour and we have been actively researching selective delivery of cytotoxic drugs for several years. Funded by the Prostate Cancer Charity, we are constructing polymeric prodrugs which release their load of extreme cytotoxins selectively in prostate tumours, through retention by the EPR effect and cleavage by the protease PSA.

Tuberculosis

Building on previous experience in inhibition of dihydrofolate reductase in cancer, we are using structure-based drug design to develop selective inhibitors of this enzyme in Mycobacterium tuberculosis.

Natural products

Collaborating with Aberystwyth University, we identify and profile natural product cinnamates from cultivated grasses, for industrial applications.

Earlier projects

Inhibitors of NOS, sirtuins, Pin1; isotopic synthesis; gene delivery; sulfoximine chemistry; biochemical kinetic isotope effects.

Publications

Jevglevskis, M., Lee, G. L., Nathubhai, A., Petrova, Y., James, T., Threadgill, M., Woodman, T. and Lloyd, M., 2017. A novel colorimetric assay for α-methylacyl-CoA racemase 1A (AMACR; P504S) utilizing the elimination of 2,4-dinitrophenolate. Chemical Communications, 53 (37), pp. 5087-5090.

Nathubhai, A., Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M., Holman, G., Pihlajaniemi, T., Tosh, D., Lehtio, L. and Threadgill, M., 2017. Highly potent and isoform-selective dual-site-binding tankyrase/Wnt signaling inhibitors that increase cellular glucose uptake and have anti-proliferative activity. Journal of Medicinal Chemistry, 60 (2), pp. 814-820.

Nathubhai, A., Haikarainen, T., Hayward, P. C., Munoz-Descalzo, S., Thompson, A. S., Lloyd, M. D., Lehtio, L. and Threadgill, M., 2016. Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases. European Journal of Medicinal Chemistry, 118, pp. 316-327.

Jevglevskis, M., Lee, G. L., Woodman, T., Nathubhai, A., Threadgill, M., James, T., Lloyd, M. and Petrova, Y., 2016. A Convenient Colorimetric Assay For Alpha-Methylacyl-Coa Racemase (AMACR; P504S) And Testing Of Inhibitors. In: RICT 2016 Interfacing Chemical Biology and Drug Discovery, 2016-07-06 - 2016-09-08.

Jevglevskis, M., Lee, G. L., Nathubhai, A., James, T., Threadgill, M., Woodman, T. and Lloyd, M., 2016. A convenient colorimetric assay for alpha-methylacyl-CoA racemase (AMACR; P504S) and testing for inhibitors.

Yang, X., Li, M., Wang, Y.-L., Threadgill, M., Han, J.-Y., Han, X., Chen, L., Chen, H., Hu, W.-P. and Lin, X., 2016. ART1 induces aberrant methylation of uPA promoter: a preliminary study. International Journal of Clinical and Experimental Pathology, 9 (4), pp. 4269-4282.

Jevglevskis, M., Lee, G. L., Nathubhai, A., James, T., Threadgill, M., Woodman, T. and Lloyd, M., 2016. A Convenient Colorimetric Assay for α-Methylacyl-CoA Racemase (AMACR; P504S) and Testing Of Inhibitors. In: Cancer Research @ Bath 13th symposium, 2016-04-27 - 2016-04-27, University of Bath.

Parveen, I., Donnison, I. S., Insole, J., Winters, A. L., Dalton, S. J., Woodman, T. and Threadgill, M., 2016. An efficient assay for ferulic acid esterase and para-coumaric acid esterases in plants at physiologically relevant activities. Chemistry & Biology Interface, 6 (5), pp. 300-311.

Jevglevskis, M., Lee, G. L., Nathubhai, A., James, T., Threadgill, M., Woodman, T. and Lloyd, M., 2015. A Convenient Colorimetric Assay for α-Methylacyl-CoA Racemase (AMACR; P504S) and Testing Of Inhibitors. In: Cancer Research @ Bath symposium, 2015-11-11 - 2015-11-11, University of Bath, Claverton Down cmpus, builidng 5W.

Threadgill, M. D., 2015. 5-Aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of the poly(ADP-ribose)polymerases (PARPs). Current Medicinal Chemistry, 22 (33), pp. 3807-3829.

Paine, H. A., Nathubhai, A., Woon, E. C. Y., Sunderland, P. T., Wood, P. J., Mahon, M. F., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Narwal, M., Lehtio, L. and Threadgill, M. D., 2015. Exploration of the nicotinamide-binding site of the tankyrases, identifying 3-arylisoquinolin-1-ones as potent and selective inhibitors in vitro. Bioorganic and Medicinal Chemistry, 23 (17), pp. 5891-5908.

Lloyd, Matthew, 2015. methods (AMACR):None. C122Q 1/533- WO 2015 /114383 A1, 06 August 2015.

Twum, E. A., Nathubhai, A., Wood, P. J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2015. Initial development of a cytotoxic amino-seco-CBI warhead for delivery by prodrug systems. Bioorganic and Medicinal Chemistry, 23 (13), pp. 3481-3489.

Kumpan, K., Nathubhai, A., Zhang, C., Wood, P. J., Lloyd, M. D., Thompson, A. S., Haikarainen, T., Lehtio, L. and Threadgill, M. D., 2015. Structure-based design, synthesis and evaluation in vitro of arylnaphthyridinones, arylpyridopyrimidinones and their tetrahydro derivatives as inhibitors of the tankyrases. Bioorganic and Medicinal Chemistry, 23, pp. 3013-3032.

Tang, Y., Li, M., Threadgill, M., Xiao, M., Mou, C.-F., Song, G.-L., Kuang, J., Yang, X., Yang, L., Gao, X.-J., Wang, Y.-P. and Meng, Y.-P., 2015. ART1 promotes starvation-induced autophagy: a possible protective role in the development of colon carcinoma. American Journal of Cancer Research, 5 (2), pp. 498-513.

Kenny, M. B. C., Cheng, K. K. Y., Cheung, J. Y. C., Fung, S. K. M., Kumpan, E., Nathubhai, A. and Threadgill, M. D., 2015. Comparison of the inhibition of tankyrase-2 by 2-aryl-7,8-dihydrothiopyrano[4,3-d]pyrimidin-4-ones and 2-aryl-5,6,7,8-tetrahydroquinazolin-4-ones. In: 23rd Conference of the Groupement des Pharmacochimistes de l’Arc Atlantique (GP2A), 2015-08-26 - 2015-08-27.

Lee, G. L., Jevglevskis, M., Threadgill, M., Woodman, T. and Lloyd, M., 2015. New routes to fight castrate-resistant prostate cancer: targeting α-methylacyl-CoA racemase (AMACR). In: 10th CR@B (Cancer Research at Bath) symposium, 2014-11-12 - 2014-11-12, University of Bath.

Lee, G. L., Jevglevskis, M., Threadgill, M., Woodman, T. and Lloyd, M., 2015. New routes to fight castrate-resistant prostate cancer: targeting α-methylacyl-CoA racemase (AMACR). In: European School of Medicinal Chemistry, 2015-06-28 - 2015-07-03.

Jevglevskis, M., Lee, G. L., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2014. The perils of rational design – unexpected irreversible elimination of fluoride from 3-fluoro-2-methylacyl-CoA esters catalysed by α-methylacyl-CoA racemase (AMACR; P504S). Chemical Communications, 50 (91), pp. 14164-14166.

Jevglevskis, M., Bowskill, C.R., Chan, C.C.Y., Heng, J.H.-J., Threadgill, M. D., Woodman, T.J. and Lloyd, M.D., 2014. A study on the chiral inversion of mandelic acid in humans. Organic and Biomolecular Chemistry, 12 (34), pp. 6737-6744.

Parveen, I., Wilson, T., Threadgill, M.D., Luyten, J., Roberts, R.E., Robson, P.R.H., Donnison, I.S., Hauck, B. and Winters, A.L., 2014. Screening for potential co-products in a Miscanthus sinensis mapping family by liquid chromatography with mass spectrometry detection. Phytochemistry, 105, pp. 186-196.

Jevglevskis, M., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2014. A novel elimination reaction catalysed by human alpha-methylacyl-CoA racemase (AMACR; P504S) and potential applications for measuring enzyme activity. In: Early Career Researchers Day, Prostate Cancer UK, 2014, 2014-03-20.

Jevglevskis, M., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2014. A novel elimination reaction catalysed by human alpha-methylacyl-CoA racemase (AMACR; P504S) and potential applications for measuring enzyme activity. In: RSC Chemical Biology and Bio-Organic Chemistry Postgraduate Symposium, 2014, 2014-04-01, University of Warwick.

Jevglevskis, M., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2014. A novel elimination reaction catalysed by human alpha-methylacyl-CoA racemase (AMACR; P504S) and potential applications for measuring enzyme activity. In: Oslo Prostate Cancer Symposium, University of Oslo, Norway, 2014-05-14 - 2014-05-16, University of Oslo.

Nathubhai, A., Wood, P. J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2013. Design and discovery of 2‑arylquinazolin-4-ones as potent and selective inhibitors of tankyrases. ACS Medicinal Chemistry Letters, 4 (12), pp. 1173-1177.

Qu, X., Allan, A., Chui, G., Hutchings, T. J., Jiao, P., Johnson, L., Leung, W. Y., Li, P. K., Steel, G. R., Thompson, A. S., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2013. Hydrolysis of ibuprofenoyl-CoA and other 2-APA-CoA esters by human acyl-CoA thioesterases-1 and -2 and their possible role in the chiral inversion of profens. Biochemical Pharmacology, 86 (11), pp. 1621-1625.

Woon, E. C. Y., Sunderland, P. T., Paine, H. A., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2013. One-pot tandem Hurtley–retro-Claisen–cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs. Bioorganic and Medicinal Chemistry, 21 (17), pp. 5218-5227.

Yan, J., Li, M., Threadgill, M.D., Wang, Y. and Fu, W., 2013. Decreasing P-selectin and ICAM-1 via activating Akt:a possible mechanism by which PARG inhibits adhesion of mouse colorectal carcinoma CT26 cells to platelets. Cancer Gene Therapy, 20 (9), pp. 487-492.

Lloyd, M. D., Jevglevskis, M., Lee, G. L., Wood, P. J., Threadgill, M. D. and Woodman, T. J., 2013. α-Methylacyl-CoA racemase (AMACR): Metabolic enzyme, drug metabolizer and cancer marker P504S. Progress in Lipid Research, 52 (2), pp. 220-230.

Twum, E. A., Woodman, T. J., Wang, W. and Threadgill, M. D., 2013. Observation by NMR of cationic Wheland-like intermediates in the deiodination of protected 1-iodo-naphthalene-2,4-diamines in acidic media. Organic and Biomolecular Chemistry, 11 (36), pp. 6208-6214.

Parveen, I., Wilson, T., Donnison, I., Cookson, A.R., Hauck, B. and Threadgill, M., 2013. Potential sources of high value chemicals from leaves, stems and flowers of Miscanthus sinensis 'Goliath' and Miscanthus sacchariflorus. Phytochemistry, 92, pp. 160-167.

Sattar, F. A., Darley, D. J., Politano, F., Woodman, T. J., Threadgill, M. D. and Lloyd, M. D., 2012. Acyl-CoA ∝-proton exchange by ∝-methylacyl-CoA racemase. In: Biochemical Society Conference,2012, 2012-01-01.

Woodman, T. J., Wood, P. J., Thompson, A. S., Hutchings, T. J., Jiao, P., Steel, G. R., Threadgill, M. D. and Lloyd, M. D., 2012. Chiral inversion of NSAID-CoA esters by human ∝-methylacyl-CoA racemase. In: Biochemical Society Conference,2012, 2012-01-01.

Qu, X., Leung, A., Allan, A. C., Chui, G., Hutchings, T. J., Jiao, P., Johnson, L., Leung, W. Y., Li, P. K., Steel, G. R., Thompson, A. S., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2012. Hydrolysis of ibuprofenoyl-CoA and other 2-APA-CoA esters by human Acyl-CoA thioesterases 1 and 2. In: Biochemical Society Conference,2012, 2012-01-01.

Parveen, I., Threadgill, M. D., Hauck, B., Donnison, I. and Winters, A., 2011. Isolation, identification and quantitation of hydroxycinnamic acid conjugates, potential platform chemicals, in the leaves and stems of Miscanthus x giganteus using LC-ESI-MS(n). Phytochemistry, 72 (18), pp. 2376-2384.

Beauchard, A., Twum, E. A., Lloyd, M. D. and Threadgill, M. D., 2011. S-2-Amino-4-cyanobutanoic acid (β-cyanomethyl-L-Ala) as an atom-efficient solubilising synthon for L-glutamine. Tetrahedron Letters, 52 (41), pp. 5311-5314.

Nathubhai, A., Patterson, R., Woodman, T. J., Sharp, H. E. C., Chui, M. T. Y., Chung, H. H. K., Lau, S. W. S., Zheng, J., Lloyd, M. D., Thompson, A. S. and Threadgill, M. D., 2011. N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides. Organic and Biomolecular Chemistry, 9 (17), pp. 6089-6099.

Woodman, T. J., Wood, P. J., Thompson, A. S., Hutchings, T. J., Steel, G. R., Jiao, P., Threadgill, M. D. and Lloyd, M. D., 2011. Chiral inversion of 2-arylpropionyl-CoA esters by human α-methylacyl-CoA racemase 1A (P504S)-a potential mechanism for the anti-cancer effects of ibuprofen. Chemical Communications, 47 (26), pp. 7332-7334.

Holbourn, K. P., Lloyd, M. D., Thompson, A. S., Threadgill, M. D. and Acharya, K. R., 2011. Cloning, purification, crystallization and preliminary crystallographic analysis of the human histone deacetylase sirtuin 1. Acta Crystallographica Section F-Structural Biology and Crystallization Communications, 67 (4), pp. 461-463.

Sunderland, P. T., Dhami, A., Mahon, M. F., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor. Organic and Biomolecular Chemistry, 9 (3), pp. 881-891.

Sunderland, P. T., Woon, E. C. Y., Dhami, A., Bergin, A. B., Mahon, M. F., Wood, P. J., Jones, L. A., Tully, S. R., Lloyd, M. D., Thompson, A. S., Javaid, H., Martin, N. M. B. and Threadgill, M. D., 2011. 5-benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2). Journal of Medicinal Chemistry, 54 (7), pp. 2049-2059.

Woodman, T.J., Wood, P. J., Thompson, A. S., Hutchings, T. J., Jiao, P., Steel, G. R., Threadgill, M. D. and Lloyd, M. D., 2011. Chiral inversion of NSAID-CoA esters by human ∝-methylacyl-CoA racemase. In: Cancer Research @ Bath Conference, 2011, 2011-05-01.

Sattar, F. A., Darley, D. J., Politano, F., Woodman, T. J., Threadgill, M. D. and Lloyd, M. D., 2010. Unexpected stereoselective exchange of straight-chain fatty acyl-CoA α-protons by human α-methylacyl-CoA racemase 1A (P504S). Chemical Communications, 46 (19), pp. 3348-3350.

Suaifan, G., Goodyer, C. L. M. and Threadgill, M. D., 2010. Synthesis of N-(Methoxycarbonylthienylmethyl)thioureas and evaluation of their interaction with inducible and neuronal Nitric Oxide Synthase. Molecules, 15 (5), pp. 3121-3134.

Kee, C. H., Ariffin, A., Awang, K., Takeya, K., Morita, H., Hussain, S. I., Chan, K. M., Wood, P. J., Threadgill, M. D., Lim, C. G., Ng, S., Weber, J. F. F. and Thomas, N. F., 2010. Challenges associated with the synthesis of unusual o-carboxamido stilbenes by the Heck protocol: Intriguing substituent effects, their toxicological and chemopreventive implications. Organic and Biomolecular Chemistry, 8 (24), pp. 5646-5660.

Parveen, I., Threadgill, M. D., Moorby, J. M. and Winters, A., 2010. Oxidative phenols in forage crops containing polyphenol oxidase enzymes. Journal of Agricultural and Food Chemistry, 58 (3), pp. 1371-1382.

Cai, L., Threadgill, M. D., Wang, Y. L. and Li, M., 2009. Effect of poly (ADP-ribose) polymerase-1 inhibition on the proliferation of murine colon carcinoma CT26 cells. Pathology & Oncology Research, 15 (3), pp. 323-328.

Dhami, A., Mahon, M. F., Lloyd, M. D. and Threadgill, M. D., 2009. 4-Substituted 5-nitroisoquinolin-1-ones from intramolecular Pd-catalysed reaction of N-(2-alkenyl)-2-halo-3-nitrobenzamides. Tetrahedron, 65 (24), pp. 4751-4765.

Lord, A.-M., Mahon, M. F., Lloyd, M. D. and Threadgill, M. D., 2009. Design, synthesis, and evaluation in vitro of quinoline-8-carboxamides, a new class of poly(adenosine-diphosphate-ribose)polymerase-1 (PARP-1) inhibitor. Journal of Medicinal Chemistry, 52 (3), pp. 868-877.

Darley, D. J., Butler, D. S., Prideaux, S. J., Thornton, T. W., Wilson, A. D., Woodman, T. J., Threadgill, M. D. and Lloyd, M. D., 2009. Synthesis and use of isotope-labelled substrates for a mechanistic study on human α-methylacyl-CoA racemase 1A (AMACR; P504S). Organic and Biomolecular Chemistry, 7 (3), pp. 543-552.

Li, M., Threadgill, M. D., Wang, Y. L., Cai, L. and Lin, X., 2009. Poly(ADP-Ribose) Polymerase Inhibition Down-Regulates Expression of Metastasis-Related Genes in CT26 Colon Carcinoma Cells. Pathobiology, 76 (3), pp. 108-116.

Beauchard, A., Phillips, V. A., Lloyd, M. D. and Threadgill, M. D., 2009. Synthesis of 2-(4-carboxybutenyl)- and 2-(4-carboxybutynyl)-cyclopentene-1-carboxamides. Tetrahedron, 65 (39), pp. 8176-8184.

Hendryk, S., Czuba, Z. P., Jędrzejowska-Szypułka, H., Szliszka, E., Phillips, V. A., Threadgill, M. D. and Król, W., 2008. Influence of 5-aminoisoquinolin-1-one (5-AIQ) on neutrophil chemiluminescence in rats with transient and prolonged focal cerebral ischaemia and after reperfusion. Journal of Physiology and Pharmacology, 59 (4), pp. 811-822.

Darley, D. J., Prideaux, S. J., Thornton, T. W., Wilson, A. D., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2008. Synthesis of 2-[2H]-2-[13C]-S-2-methyldecanoyl-CoA and 13C NMR study of its reaction with ∝-methylacyl-CoA racemase (AMACR.

Darley, D. J., Butler, D. S., Threadgill, M. D. and Lloyd, M. D., 2008. Characterisation of recombinant alpha-methylacyl-CoA racemase, a novel prostate cancer target. In: RSC Bioorganic Group Annual Post-Graduate Symposium P7, 2008, 2008-03-01.

Darley, D. J., Prideaux, S. J., Thornton, T. W., Wilson, A. D., Threadgill, M. D., Woodman, T. J. and Lloyd, M. D., 2008. Synthesis of 2-[2H]-2-[13C]-S-2-methyldecanoyl-CoA and 13C NMR study of its reaction with ∝-methylacyl-CoA racemase (AMACR. In: RSC Bioorganic Group Annual Post-Graduate Symposium P8, 2008, 2008-03-01.

Beauchard, A., Phillips, V. A., Lloyd, M. D. and Threadgill, M. D., 2008. Synthesis of a mimic of phosphorserylproline as a potential inhibitor of Pin1. In: RSC Bioorganic Group Annual Post-Graduate Symposium P13, 2008, 2008-03-01.

Parveen, I., Winters, A., Threadgill, M. D., Hauck, B. and Morris, P., 2008. Extraction, structural characterisation and evaluation of hydroxycinnamate esters of orchard grass (Dactylis glomerata) as substrates for polyphenol oxidase. Phytochemistry, 69 (16), pp. 2799-2806.

Lloyd, M. D., Darley, D. J., Wierzbicki, A. S. and Threadgill, M. D., 2008. α-Methylacyl-CoA racemase - an 'obscure' metabolic enzyme takes centre stage. FEBS Journal, 275, pp. 1089-1102.

This list was generated on Mon May 29 08:47:08 2017 IST.

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