Prof. Dave Adams BSc, PhD, CChem, MRSC

• Section Head, Organic Chemistry
• William Perkin Building Safety Officer
• HWU Life Sciences Interface Theme management team member
• EPS Undergraduate Studies Group Chemistry representative
• Chemistry Research Committee

Biological and Medicinal Chemistry

The identity and status of cells is largely defined by complex communication processes that occur between and within them; dysfunction in these processes underpins much of human disease. Thus, our research is mainly focused on exploration and therapeutic manipulation of cellular signalling pathways. We design compounds for therapeutic use and as probes to investigate structure & function of signalling proteins, collaborating with molecular biologists to understand protein regulatory mechanisms.

1. Ligand Regulation of G-Protein Coupled Receptors (GPCRs)

GPCRs are a large family of transmembrane receptors that mediate signalling by numerous hormones and neurotransmitters. We develop conformationally-constrained probe compounds to investigate ligand binding properties at chemoattractant GPCRs such as FFA2 (GPR43, free fatty acid receptor) and CXCR2 (chemokine receptor).

Figure 1. Ligands for 7-TM GPCRs are used for probing cellular signalling pathways and have potential therapeutic utility.

2. Phosphodiesterase (PDE) Signalling

The activity of many GPCRs is transduced through the intracellular second messenger, cAMP. PDE enzymes downregulate cAMP, mediating its hydrolysis to AMP. Tight spatiotemporal control of [cAMP] gradients is essential for cell function and is afforded by subcellular localisation of PDEs to signalling complexes. We develop PDE4 ligands to investigate their therapeutic utility, to probe the mechanism of cross-talk between enzyme catalytic and regulatory domains, and to probe PDE4-protein binding.

 

Figure 2. PDE enzymes play pivotal roles in controlling cell function and are important therapeutic targets.

3. RACK1-Scaffolded Signalling

RACK1 is a 7-bladed beta-propeller protein that acts as a scaffolding hub and orchestrates formation of signalling complexes, e.g. at focal adhesions, where it interacts with cell surface integrins and IGF1R, modulating phosphorylation of focal adhesion kinase (FAK) and paxillin. As such, it regulates cell migration relevant to cancer cell metastasis. We are interested in defining RACK1 loci involved in protein associations and in developing compounds that modulate those associations.

Figure 3. cAbl kinase phosphorylates RACK1 on Tyr52 (yellow stick) and is required for IGF1R-mediated regulation of FAK.

1. 'Extracellular loop 2 of the free fatty acid receptor 2 mediates allosterism of a phenylacetamide ago-allosteric modulator', N. J. Smith, R. J. Ward, L. A. Stoddart, B. D. Hudson, E. Kostenis, T. Ulven, J. C. Morris, C. Trankle, I. G. Tikhonova, D. R. Adams and G. Milligan, Mol. Pharmacol., 2011, in press (doi:10.1124/mol.110.070789).
2. 'Phosphodiesterase inhibitors. Part 1: Synthesis and structure-activity relationships of pyrazolopyridine-pyridazinone PDE inhibitors developed from ibudilast',  R. W. Allcock, H. Blakli, Z. Jiang, K. A. Johnston, K. M. Morgan, G. M. Rosair, K. Iwase, Y. Kohno and D. R. Adams, Bioorg. Med. Chem. Lett., 2011, 21, 3307.
3. 'Elucidation of a structural basis for the inhibitor-driven, p62 (SQSTM1)-dependent intracellular redistribution of cAMP phosphodiesterase-4A4 (PDE4A4)', J. P. Day, B. Lindsay, T. Riddell, Z. Jiang, R. W. Allcock, A. Abraham, S. Sookup, F. Christian, J. Bogum, E. K. Martin, R. L. Rae, D. Anthony, G. M. Rosair, D. M. Houslay, E. Huston, G. S. Baillie, E. Klussmann, M. D. Houslay and D. R. Adams, J. Med. Chem., 2011, 54, 3331.
4. 'Disruption of the cyclic AMP phosphodiesterase-4 (PDE4)-HSP20 complex attenuates the beta-agonist induced hypertrophic response in cardiac myocytes', Y. Y. Sin, H. V. Edwards, X. Li, J. P. Day, F. Christian, A. J. Dunlop, D. R. Adams, M. Zaccolo, M. D. Houslay and G. S. Baillie, J. Mol. Cell. Cardiol., 2011, 50, 872.
5. 'Phosphorylation of RACK1 on tyrosine 52 by c-Abl is required for insulin-like growth factor I-mediated regulation of focal adhesion kinase', P. A. Kiely, G. S. Baillie, R. Barrett, D. A. Buckley, D. R. Adams, M. D. Houslay and R. O'Connor, J. Biol. Chem., 2009, 284, 20263.