HTS Screening for Glutaminase Inhibitors

描述(申请人提供)：这项提案的总体目标是通过NIH化学文库的高通量筛选(HTS)来鉴定谷氨酰胺酶小分子抑制剂。谷氨酰胺酶已被确定为治疗cMyc表达的癌症的靶点，最近发现这种上调的酶在促进癌细胞生长方面发挥着关键的代谢作用。最近还发现，谷氨酰胺酶在激活的巨噬细胞/小胶质细胞中上调，其抑制限制了谷氨酸的释放，并在炎症性神经疾病中提供神经保护，如HIV1相关性痴呆和多发性硬化症。到目前为止，还没有已知的有效的和选择性的谷氨酰胺酶抑制剂。我们建议对NIH化学文库进行筛选，以获得可用作工具分子的HITS，以进一步研究该靶点的药理作用，并为进一步将化学优化为类药物抑制剂用于临床开发提供线索。 与公共卫生相关：最近发现，在炎症性神经疾病中，如HIV1相关性痴呆和多发性硬化症，谷氨酰胺酶在癌细胞和激活的小胶质细胞中上调。降低谷氨酰胺酶的遗传方法已被证明可以抑制癌细胞的增殖并提供神经保护。然而，到目前为止，还没有这种酶的选择性小分子抑制剂。新型谷氨酰胺酶抑制剂的发现将为这些疾病的治疗提供新的策略。

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.