HTS Screening for Glutaminase Inhibitors

描述（由申请方提供）：本提案的总体目的是通过NIH化学品库的高通量筛选（HTS）鉴定转氨酶的小分子抑制剂。谷氨酰胺酶已被鉴定为用于治疗cMyc表达癌症的靶标，其中上调的酶最近已被证明在促进癌细胞生长中发挥关键的代谢作用。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，其抑制限制谷氨酸释放，并在炎性神经系统疾病如HIV 1相关痴呆和多发性硬化中提供神经保护。迄今为止，还没有已知的有效的和选择性的转氨酶抑制剂可用。我们建议筛选NIH化学文库，以获得可用作工具分子的“命中”，以进一步研究该靶标的药理学，并作为进一步化学优化为药物样抑制剂用于临床开发的线索。 公共卫生相关性：谷氨酰胺酶最近被证明是上调的癌细胞和激活的小胶质细胞在炎症性神经系统疾病，如艾滋病毒1相关的痴呆症和多发性硬化症。降低转氨酶的遗传方法已被证明可以抑制癌细胞增殖并提供神经保护。然而，迄今为止，没有这种酶的选择性小分子抑制剂。鉴定新的转氨酶抑制剂将为这些疾病提供新的治疗策略。

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.