Deadenylase enzymes as potential novel drug targets in osteoporosis, bone disease, and repair
Lead Research Organisation:
University of Nottingham
Department Name: Sch of Pharmacy
Abstract
In the UK, women over 45 years old spend more time in hospital due to osteoporosis than heart disease, diabetes or breast cancer. Common hip, wrist, and spinal bone fractures due to decreased bone density are a huge financial cost to the NHS and impact significantly on morbidity and the quality of life, in particular of women and the elderly. Although several options are available for the prevention and treatment of osteoporosis, currently available drugs are not always effective. Moreover, not all patients tolerate the available medications due to side-effects.
If successful, our project is the first step towards novel drugs of the future that may be useful for the treatment of osteoporosis, bone disease and repair. These future drugs will have more desirable characteristics compared to current medications. They will be available as tablets, have fewer side-effects and enhance bone formation directly by stimulating bone-forming cells. The idea behind the selection of the enzyme target in bone-forming cells comes from genetically engineered mice with heavy bones and studying the relevant enzymes in great detail. We will search for drug-like molecules by screening a large collection of thousands of compounds using robots. In parallel, we will use high-performance computer clusters to screen a database with information of up to 1 million compounds using ?cheminformatics?. We will then optimise our hits using synthetic chemistry and test the activity of our compounds by looking at bone formation in cell culture dishes. If successful, our research will identify molecules that may represent candidates for future drug development.
If successful, our project is the first step towards novel drugs of the future that may be useful for the treatment of osteoporosis, bone disease and repair. These future drugs will have more desirable characteristics compared to current medications. They will be available as tablets, have fewer side-effects and enhance bone formation directly by stimulating bone-forming cells. The idea behind the selection of the enzyme target in bone-forming cells comes from genetically engineered mice with heavy bones and studying the relevant enzymes in great detail. We will search for drug-like molecules by screening a large collection of thousands of compounds using robots. In parallel, we will use high-performance computer clusters to screen a database with information of up to 1 million compounds using ?cheminformatics?. We will then optimise our hits using synthetic chemistry and test the activity of our compounds by looking at bone formation in cell culture dishes. If successful, our research will identify molecules that may represent candidates for future drug development.
Technical Summary
In this proof of concept project, we shall explore the development of small-molecule inhibitors of deadenylase enzymes as a novel therapeutic approach for bone-related diseases, such as osteoporosis. We hypothesise that small-molecule inhibitors of deadenylase enzymes involved in mRNA degradation lead to increased osteoblast activity, will enhance bone density in osteoporotic bone, and promote the healing of bone fractures. The basis for this hypothesis is the observation that the CNOT7 deadenylase is a repressor of osteoblast cell activity as exemplified by the observation that CNOT7-null mice have increased bone density. Similar effects on bone are observed in mice lacking the Tob protein, which interacts with the CNOT7 gene product as a positive regulator. The CNOT7 protein is a poly(A) ribonuclease involved in cytoplasmic mRNA degradation that acts as a repressor of bone morphogenic protein-mediated signalling in osteoblasts.
We aim to identify small-molecule deadenylase inhibitors using an interdisciplinary approach that brings together expertise in the biochemistry and cell biology of gene regulation, the biology of osteoblast cells and bone tissue, and screening capabilities and medicinal chemistry at the University of Nottingham. We shall use complementary approaches to maximise the potential of identifying small-molecule inhibitors. In addition to virtual ligand screening based on high-resolution crystal structures that are available in the public domain, we will develop and deploy a fluorescent deadenylase assay screen of an extensive, chemically diverse library of small drug-like molecules using robotics. Hit compounds will be verified and their selectivity determined using secondary biochemical and cell-based screens with a range of deadenylase enzymes. Hit-to-lead conversion medicinal chemistry will be carried out and lead compounds will be profiled extensively in terms of target and cell potency, selectivity, specificity, and pharmacological action, including the use of human and rodent osteoblast cells. If successful, this strategy will identify lead compounds that can modulate bone formation in cell-based models in a manner that suggests potential therapeutic use, and that may represent candidates for future drug development. Furthermore, such compounds will have much wider use as chemical probes in molecular and cellular medicine.
We aim to identify small-molecule deadenylase inhibitors using an interdisciplinary approach that brings together expertise in the biochemistry and cell biology of gene regulation, the biology of osteoblast cells and bone tissue, and screening capabilities and medicinal chemistry at the University of Nottingham. We shall use complementary approaches to maximise the potential of identifying small-molecule inhibitors. In addition to virtual ligand screening based on high-resolution crystal structures that are available in the public domain, we will develop and deploy a fluorescent deadenylase assay screen of an extensive, chemically diverse library of small drug-like molecules using robotics. Hit compounds will be verified and their selectivity determined using secondary biochemical and cell-based screens with a range of deadenylase enzymes. Hit-to-lead conversion medicinal chemistry will be carried out and lead compounds will be profiled extensively in terms of target and cell potency, selectivity, specificity, and pharmacological action, including the use of human and rodent osteoblast cells. If successful, this strategy will identify lead compounds that can modulate bone formation in cell-based models in a manner that suggests potential therapeutic use, and that may represent candidates for future drug development. Furthermore, such compounds will have much wider use as chemical probes in molecular and cellular medicine.