Dr Amit Nathubhai

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.

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/β-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/β-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 β-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/β-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/β-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/β-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.

• 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