具有水溶性的糖缀合 SIRT2 抑制剂允许基于结构的 SIRT2 抑制剂设计。,ACS Chemical Biology

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具有水溶性的糖缀合 SIRT2 抑制剂允许基于结构的 SIRT2 抑制剂设计。
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2019-08-02 , DOI: 10.1021/acschembio.9b00384
Jun Young Hong ₁ , Ian Robert Price ₁ , Jessica Jingyi Bai ₁ , Hening Lin _{1,

2}

Affiliation

SIRT2 的小分子抑制剂是烟酰胺腺嘌呤二核苷酸依赖性蛋白赖氨酸脱酰酶的 sirtuin 家族的成员，已显示出治疗癌症和神经退行性疾病的希望。开发具有更好药理特性的 SIRT2 选择性抑制剂是进一步实现靶向 SIRT2 治疗潜力的关键。已报道的最好的 SIRT2 选择性抑制剂之一是一种名为 TM 的硫代肉豆蔻酰赖氨酸化合物，它在小鼠模型中显示出有前途的抗癌活性，对正常细胞没有太大毒性。然而，TM 的主要局限性是水溶性低和缺乏 X 射线晶体结构来帮助未来的药物设计。在这里，我们设计并合成了一种具有优异水溶性的葡萄糖缀合 TM (glucose-TM) 类似物。虽然 glucose-TM 不具有细胞渗透性，优异的水溶性使我们能够获得与其复合的 SIRT2 的晶体结构。该结构使我们能够设计出几种新的 TM 类似物，其中之一 NH4-6 在细胞培养中显示出优异的水溶性和更好的抗癌活性。这些研究的结果提供了重要的见解，将进一步推动改进的 SIRT2 抑制剂作为治疗癌症和神经退行性变的有前途的疗法的未来发展。

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A Glycoconjugated SIRT2 Inhibitor with Aqueous Solubility Allows Structure-Based Design of SIRT2 Inhibitors.

Small molecule inhibitors for SIRT2, a member of the sirtuin family of nicotinamide adenine dinucleotide-dependent protein lysine deacylases, have shown promise in treating cancer and neurodegenerative diseases. Developing SIRT2-selective inhibitors with better pharmacological properties is key to further realize the therapeutic potential of targeting SIRT2. One of the best SIRT2-selective inhibitors reported is a thiomyristoyl lysine compound called TM, which showed promising anticancer activity in mouse models without much toxicity to normal cells. The main limitations of TM, however, are the low aqueous solubility and lack of X-ray crystal structures to aid future drug design. Here, we designed and synthesized a glucose-conjugated TM (glucose-TM) analog with superior aqueous solubility. Although glucose-TM is not cell permeable, the excellent aqueous solubility allowed us to obtain a crystal structure of SIRT2 in complex with it. The structure enabled us to design several new TM analogs, one of which, NH4-6, showed superior water solubility and better anticancer activity in cell culture. The results of these studies provided important insights that will further fuel the future development of improved SIRT2 inhibitors as promising therapeutics for treating cancer and neurodegeneration.

更新日期：2019-08-02

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