Dr D J Watts
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Bisphosphonate drugs have been in use for over 20 years for treatment of conditions in which there is excessive bone resorption e.g. Paget's disease, tumoral bone disease. Further developments have since led to the introduction of the extremely potent aminobisphosphonate drugs, particularly for the treatment of osteoporosis which is common in elderly people and in patients treated with glucocorticoids to relieve the effects of severe arthritis. The latter drugs now have sales well in excess of $1 billion per year. |
| The drugs act on the osteoclasts in bone but these cells are difficult to study in vitro. Instead, my research group found that the bisphosphonates also inhibit axenic growth of the amoeboid micro-organism Dictyostelium discoideum and comparison of structure-activity relationships for a wide variety of bisphosphonates as inhibitors of bone resorption and as inhibitors of Dictyostelium growth indicated that the bisphosphonates had the same mechanism of action in Dictyostelium as in osteoclasts. Use of Dictyostelium as a convenient model system then allowed us to prove that the target for the aminobisphosphonates is the enzyme farnesyl diphosphate synthase and it has since been confirmed that this enzyme is also the target in osteoclasts. However, it appears that there are further targets involved in the action of the aminobisphosphonates and we are currently seeking to identify these. |
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Figure Legend - Dictyostelium is also used as a model system for studies of development and differentiation since, on starvation, the amoebae form aggregates that transform into fruiting bodies in which the original amoebae have differentiated into stalk cells and spores. The scanning electron micrograph shows a group of aggregates. |
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Selected Publications
Determination of the microscopic equilibrium dissociation constants for risedronate and its analogues reveals two distinct roles for the nitrogen atom in nitrogen-containing bisphosphonate drugs. Hounslow AM, Carran J, Brown RJ, Rejman D, Blackburn GM, Watts DJ J Med Chem. 2008 Jul 24;51(14):4170-8. |
| Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mould Dictyostelium discoideum. M.J.Rogers, D.J.Watts, R.G.G.Russell, X.Ji, X.Xiong, G.M.Blackburn, A.V.Bayless and F.H.Ebetino (1994). Journal of Bone and Mineral Research 9, 1029-1039. |
| Structure-activity relationships of new heterocycle-containing bisphosphonates as inhibitors of bone resorption and as inhibitors of growth of Dictyostelium discoideum amoebae. M.J.Rogers, X.Xiong, R.J.Brown, D.J.Watts, R.G.G.Russell, A.V.Bayless and F.H.Ebetino (1995) Molecular Pharmacology, 47, 398-402. |
| The intracellular target for the antiresorptive aminobisphosphonate drugs in Dictyostelium discoideum is the enzyme farnesyl diphosphate synthase. J.E.Grove, R.J.Brown, D.J.Watts (2000) Journal of Bone and Mineral Research 15, 971-981. |
