Senior Lecturer in Medicinal Chemistry
Our research involves the design, synthesis and biological evaluation of novel molecular tools, to selectively inhibit key pharmacological targets that are implicated towards the progression of particular diseases.
My aim is to improve the diagnosis and treatment of patients, by using rational drug design coupled with controlled pharmacological intervention.
Teaching and supervision
I currently teach organic, medicinal and biological chemistry to students enrolled on MPharm, Biopharmaceutical Science, Cosmetic Science and also teach students on MSc Drug Discovery and Development.
Research interests for potential research students
Prospective research students would be working in an interdisciplinary environment at the interface of chemistry and biology. Research projects are focused on the development of our current panel of tankyrase inhibitors into novel “drug-like” molecules that can:
- Inhibit Wnt/ß-catenin signalling during colorectal and/or prostate cancer
- Modulate a molecular pathway involved in insulin-stimulated glucose uptake
- Be used in regenerative medicine.
The enzymes called tankyrases (TNKSs) have been shown to regulate many cellular mechanisms. At elevated levels, these cellular mechanisms contribute towards various diseases. My research focuses on the design, synthesis and biological evaluation of selective inhibitors of the Tankyrases (TNKSs) in order to understand their role during colorectal cancer, prostate cancer, diabetes and obesity. TNKSs are members of the poly(ADP-ribose)-polymerase (PARP) family of 17 enzymes. There are two human isoforms of TNKSs, TNKS1 (PARP5a) and TNKS2 (PARP5b). Both TNKS1 and TNKS2 use the substrate nicotinamide adenosine dinucleotide (NAD+), which binds to the nicotinamide and adenosine binding domains of TNKS. Binding of NAD+ transfers adenosine diphosphate-ribose (ADP-ribose) units to target proteins. Target proteins include telomere repeating binding factor-1 (TRF1), nuclear mitotic apparatus protein (NuMA, which is essential for the resolution of chromatids during mitosis), and axin to regulate Wnt/ß-catenin signalling. Increased Wnt signalling correlates with over-expression of TNKSs in several human cancers, and inhibition of TNKSs is reported to lead to stabilization of axin causing decreased nuclear ß-catenin-driven proliferation of cancer cells.
Insulin-regulated aminopeptidase (IRAP) is also a binding partner and target protein of TNKSs. Together, IRAP and TNKSs can enhance insulin-stimulated exocytosis of GLUT4, which could result in increased uptake of glucose. TNKS-knockout mice have shown to display increased sensitivity to insulin and reduced adiposity regardless of calorie intake. However, studies to investigate the role of TNKSs during the translocation of GLUT4 have been limited to the use of pan-PARP inhibitors.
We have recently prepared a panel of potent and isoform-selective TNKS inhibitors. The crystal structures of our TNKS inhibitors bound into the catalytic domain of TNKS2, confirmed that they occupy the nicotinamide and adenosine-binding site as designed. Our current panel of TNKS inhibitors demonstrate:
i) Potent inhibition of cellular Wnt/ß-catenin signalling in vitro.
ii) Significant antiproliferative activity of human colon carcinoma and prostate cancer cells cells in vitro.
iv) Enhanced insulin-stimulated glucose uptake.
We are now using our panel of TNKS inhibitors as molecular tools to dissect the fundamental mechanisms that contribute towards certain cancers and enhanced glucose uptake. We now aim to develop our current panel of compounds into “drug-like” molecules, in order to progress our inhibitors towards the clinic.
Impact of our research:
Together, bowel, colon and gastric cancer is the second biggest killing cancer in the UK, and 50% of colorectal cancer patients die within 5 years from diagnosis. Around 90% of colorectal cancers occur via aberrant Wnt/ß-catenin signalling, and studies reveal that this signalling pathway may play a crucial role during the development of prostate cancer. Therefore, new methods to inhibit Wnt/ß-catenin-mediated colorectal and prostate cancer could benefit many patients.
It is estimated that 5 million people will have type-1 and type-2 diabetes by 2025. Currently, £10 billion (10% of the NHS budget) is being spent on treating diabetes and diabetic related diseases. New methods to enhance glucose tolerance and reduce adiposity would have a significant benefit to many patients and save our NHS a considerable amount of money.
Petrova, Yoana, D., Wadda, Katty, Nathubhai, Amit, Yevglevskis, Maksims, Mitchell, Paul, J., James, Tony, D., Threadgill, Michael, D., Woodman, Timothy, J. and Lloyd, Matthew, D. (2019) Identification of novel small-molecule inhibitors of α-methylacyl-CoA racemase (AMACR; P504S) and structure activity relationships. Bioorganic Chemistry, 92 (103264). pp. 1-6. ISSN 0045-2068
Yevglevskis, Maksims, Nathubhai, Amit, Wadda, Katty, Lee, Guat, Al-Rawi, Suzanne, Jiao, Tingying, Mitchell, Paul, J., James, Tony, D., Threadgill, Michael, D., Woodman, Timothy, J. and Lloyd, Matthew, D. (2019) Novel 2-arylthiopropanoyl-CoA inhibitors of α-methylacyl-CoA racemase 1A (AMACR; P504S) as potential anti-prostate cancer agents. Bioorganic Chemistry, 92 (103263). pp. 1-8. ISSN 0045-2068
Yevglevskis, M., Lee, G. L, Nathubhai, Amit, Petrova, Y.D., James, T.D., Threadgill, M.D., Woodman, T.J and Lloyd, M.D. (2018) Structure-activity relationships of rationally designed AMACR 1A inhibitors. BIOORGANIC CHEMISTRY, 79. pp. 145-154. ISSN 0045-2068
Gravells, P., Neale, J., Grant, E., Nathubhai, Amit, Smith, K.M., James, D.I. and Bryant, H.E. (2017) Radiosensitization with an inhibitor of poly(ADP-ribose) glycohydrolase: A comparison with the PARP1/2/3 inhibitor olaparib. DNA Repair, 61. pp. 25-36. ISSN 1568-7864
Yevglevskis, M., Lee, G.L., Nathubhai, Amit, Petrova, Y.D., James, T.D., Threadgill, M.D., Woodman, T.J. and Lloyd, M.D. (2017) A novel colorimetric assay for alpha-methylacyl-CoA racemase 1A (AMACR; P504S) utilizing the elimination of 2,4-dinitrophenolate. Chemical Communications, 53 (37). pp. 5073-5240. ISSN 1359-7345
Nathubhai, Amit, Haikarainen, T., Koivunen, J., Murthy, S., Koumanov, F., Lloyd, M.D., Holman, J.D., Pihlajaniemi, T., Tosh, D., Lehtiö, L. and Threadgill, M.D. (2016) Highly Potent and Isoform Selective Dual Site Binding Tankyrase/Wnt Signaling Inhibitors That Increase Cellular Glucose Uptake and Have Antiproliferative Activity. Journal of Medicinal Chemistry, 60 (2). pp. 814-820. ISSN 0022-2623
Nathubhai, Amit, Haikarainen, T, Hayward, P.C., Munoz-Descalzo, S., Thompson, A.S., Lloyd, M.D., Lehtio, L. and Threadgill, M.D. (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. ISSN 0223-5234
Paine, H.A., Nathubhai, Amit, Woon, E.C.Y., Sunderland, P.T., Wood, P.J., Mahon, M.F., Lloyd, M.D., Thompson, A.S., Haikarainen, T., Narwal, M., Lehtiö, 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 & Medicinal Chemistry, 23. pp. 5891-5908. ISSN 0968-0896
Kumpan, K., Nathubhai, Amit, Zhang, C., Wood, P.J., Lloyd, M.D., Thompson, A.S., Haikarainen, T., Lehtiö, 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 & Medicinal Chemistry, 23. pp. 3013-3032. ISSN 0968-0896
Twum, E.A., Nathubhai, Amit, 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 & Medicinal Chemistry, 23. pp. 3481-3489. ISSN 0968-0896
Nathubhai, Amit, 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. ISSN 1948-5875
Nathubhai, Amit, Patterson, R., Woodman, T.J., Sharp, H.E.C., Chui, M.T.Y., Chung, H.H.K., Lau, 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 & Biomolecular Chemistry, 9. pp. 6089-6099. ISSN 1477-0520
Dixon, M.J., Nathubhai, Amit, Andersen, O.A., van Aalten, D.M.F. and Eggleston, I.M. (2009) Synthesis and structure-based dissection of cyclic peptide chitinase inhibitors: New leads for antifungal and anti-inflammatory drugs. Advances in Experimental Medicine and Biology, 611. pp. 525-526. ISSN 0065-2598
Dixon, M.J., Nathubhai, Amit, Andersen, O.A., van Aalten, D.M.F. and Eggleston, I.M. (2008) Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold. Organic & Biomolecular Chemistry, 7. pp. 259-268. ISSN 1477-0520
Dixon, M.J., Giuntini, F., Nathubhai, Amit, Andersen, O.A., van Aalten, D.M.F. and Eggleston, I.M. (2008) Synthetic approaches to cyclic peptide natural products as chitinase inhibitors. Journal of Peptide Science, 14 (8). p. 55. ISSN 1075-2617
Dixon, M.J., Andersen, O.A., van Aalten, D.M.F., Nathubhai, Amit and Eggleston, I.M. (2008) Synthesis of cyclic peptide chitinase inhibitors: Natural products with chemotherapeutic potential. Journal of Peptide Science, 14 (8). p. 13. ISSN 1075-2617
Andersen, O.A., Nathubhai, Amit, Dixon, M.J., Eggleston, I.M. and van Aalten, D.M.F. (2008) Structure-Based Dissection of the Natural Product Cyclopentapeptide Chitinase Inhibitor Argifin. Chemistry & Biology, 15 (3). pp. 295-301. ISSN 1074-5521
Dixon, M.J., Andersen, O.A., van Aalten, D. M. F., Nathubhai, Amit and Eggleston, I.M. (2007) Cyclic peptide chitinase inhibitors: New leads for antifungal and anti-inflammatory drugs. Biopolymers, 88 (4). p. 576. ISSN 0006-3525
Nathubhai, Amit, Threadgill, M D (2016) New potent and selective tankyrase inhibitors for the treatment of disease or conditions associated with Wnt signalling e.g. colon cancer, prostate cancer, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease and type-1/type-2 diabetes. WO2017-GB52624.
Threadgill, M D, Lloyd, M D, Thompson, A S, Nathubahai, Amit, Wood, P J, Paine, H A, Kumpan, E, Sunderland. P T, Woon, Y, Chue, E (2013) Use of new and known pyridine or pyrimidine compounds, for the treatment of a disease or condition associated with tankyrase, e.g. cancer selected from e.g. breast, colon, stomach, and liver. WO2014087165A1.
- Organic chemistry
- Medicinal chemistry
- Biological chemistry
- Associate Fellow of the Higher Education Academy
- Member of the Royal Society of Chemistry
- Reviewer for journals in the field of Medicinal Chemistry