This application is in response to program announcement PAR-03-056. One of the stated objectives of this program is """"""""Drug Development for Cognitive Decline and Alzheimer's Disease"""""""". We have been developing combinatorial approaches to activators of tyrosine kinases, which are critical mediators of hormone, growth factor and cytokine signaling. The tripartite structure of the asterriquinones is ideally suited for combinatorial synthesis and we have validated our synthetic route by synthesizing a small library of methylated analogues. This proposal will use our combinatorial methods to develop libraries of diverse asterriquinone compounds that will be screened against the NGF receptor tyrosine kinase. Our driving hypothesis has been that the asterriquinone structure has a unique ability to interact with tyrosine kinases and that a library of closely related structures would be a valuable resource for the discovery of small molecule activators of the TrkA receptor. In this proposal, we would like to explore this hypothesis by screening this combinatorial library against test tyrosine kinases. With funding from this pilot grant, we hope to generate lead compounds that are selective cell-permeable activators of the NGF receptor. These compounds would be orally available and could be used to test whether such drugs would be effective in preventing the decline in cognitive function seen in aging and Alzheimer's disease.
The Specific Aim of this proposal is to screen the combinatorial asterriquinone library against the NGF receptor.
| Pirrung, Michael C; Deng, Liu; Lin, Bo et al. (2008) Quinone replacements for small molecule insulin mimics. Chembiochem 9:360-2 |
| Pirrung, Michael C; Li, Zhitao; Hensley, Erika et al. (2007) Parallel synthesis of indolylquinones and their cell-based insulin mimicry. J Comb Chem 9:844-54 |
| Lin, Bo; Li, Zhitao; Park, Kaapjoo et al. (2007) Identification of novel orally available small molecule insulin mimetics. J Pharmacol Exp Ther 323:579-85 |
| Lin, Bo; Pirrung, Michael C; Deng, Liu et al. (2007) Neuroprotection by small molecule activators of the nerve growth factor receptor. J Pharmacol Exp Ther 322:59-69 |
