HTS Screening for Glutaminase Inhibitors

描述（由申请人提供）：本提案的总体目标是通过NIH化学文库的高通量筛选（HTS）鉴定谷氨酰胺酶的小分子抑制剂。谷氨酰胺酶已被确定为治疗表达cmyc的癌症的靶标，其中上调的酶最近被证明在促进癌细胞生长的关键代谢作用中发挥作用。谷氨酰胺酶最近也被证明在活化的巨噬细胞/小胶质细胞中上调，其抑制作用限制了谷氨酸的释放，并在炎症性神经疾病（如hiv相关痴呆和多发性硬化症）中提供神经保护。迄今为止，还没有已知的有效和选择性谷氨酰胺酶抑制剂。我们建议筛选NIH化学文库以获得可作为工具分子的“hit”，以进一步研究该靶点的药理学，并作为进一步化学优化成药物样抑制剂的先导，用于临床开发。

DESCRIPTION (provided by applicant): The overall aim of this proposal is to identify small molecule inhibitors of glutaminase through high throughput screening (HTS) of the NIH chemical library. Glutaminase has been identified as a target for the treatment of cMyc-expressing cancers where the up-regulated enzyme has recently been shown to play a critical metabolic role promoting cancer cell growth. Glutaminase has also recently been shown to be up-regulated in activated macrophages/microglia and its inhibition limits glutamate release and provides neuroprotection in inflammatory neurological disorders such as HIV1-associated dementia and multiple sclerosis. To date there are no known potent and selective glutaminase inhibitors available. We propose to screen the NIH chemical library to obtain "hits" that could be used as tool molecules to further study the pharmacology of this target as well as serve as leads for further chemical optimization into drug-like inhibitors for clinical development. PUBLIC HEALTH RELEVANCE: Glutaminase has recently been shown to be up-regulated in cancer cells and activated microglia in inflammatory neurological disorders such as HIV1-associated dementia and multiple sclerosis. Genetic approaches which decrease glutaminase have been shown to inhibit cancer cell proliferation and provide neuroprotection. To date, however, there are no selective small molecule inhibitors of this enzyme. Identification of new glutaminase inhibitors would provide a novel therapeutic strategy for these diseases.