Leucettinibs，一类 DYRK/CLK 激酶抑制剂，灵感源自海洋海绵天然产物 Leucetamine B,Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Leucettinibs，一类 DYRK/CLK 激酶抑制剂，灵感源自海洋海绵天然产物 Leucetamine B
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2023-07-24 , DOI: 10.1021/acs.jmedchem.3c00884
Emmanuel Deau ₁ , Mattias F Lindberg ₁ , Frédéric Miege ₂ , Didier Roche ₂ , Nicolas George ₃ , Pascal George ₁ , Andreas Krämer _{4,

5} , Stefan Knapp ₄ , Laurent Meijer ₁

Affiliation

双特异性酪氨酸磷酸化调节激酶 (DYRK) 和 cdc2 样激酶 (CLK) 最近因其在各种病理学中的重要参与而引起了人们的关注。我们在此描述了一系列源自亮氨酰胺和海洋天然产物亮氨酰胺 B 的 DYRK/CLK 抑制剂。合成了 45 种带有融合的 [6 + 5]-杂芳基亚甲基的N 2-官能化 2-氨基咪唑啉-4-酮。苯并噻唑-6-基亚甲基被选为 15 个不同杂芳基亚甲基中最有效的残基。合成并广泛表征了186 个带有苯并噻唑-6-基亚甲基的N 2-取代 2-氨基咪唑啉-4-酮，统称为 Leucettinib。鉴定出亚纳摩尔 IC _{50 （DYRK1A 为 0.5-20 nM）抑制剂，并在 DYRK1A 中对一种 Leucettinib 进行建模，并与 CLK1 和较弱抑制的脱靶 CSNK2A1 共结晶。}合成了 Leucettinib 的激酶失活异构体（DYRK1A 上 >3–10 μM），称为 iso-Leucettinib，并作为适合功能实验的阴性对照化合物进行表征。Leucettinib（而非 iso-Leucettinib）抑制细胞中 DYRK1A 底物的磷酸化。Leucettinib 为进一步优化候选治疗药物提供了新的研究工具和潜在线索。

"点击查看英文标题和摘要"

Leucettinibs, a Class of DYRK/CLK Kinase Inhibitors Inspired by the Marine Sponge Natural Product Leucettamine B

Dual-specificity, tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) recently attracted attention due to their central involvement in various pathologies. We here describe a family of DYRK/CLK inhibitors derived from Leucettines and the marine natural product Leucettamine B. Forty-five N2-functionalized 2-aminoimidazolin-4-ones bearing a fused [6 + 5]-heteroarylmethylene were synthesized. Benzothiazol-6-ylmethylene was selected as the most potent residue among 15 different heteroarylmethylenes. 186 N2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC₅₀ (0.5–20 nM on DYRK1A) inhibitors were identified and one Leucettinib was modeled in DYRK1A and co-crystallized with CLK1 and the weaker inhibited off-target CSNK2A1. Kinase-inactive isomers of Leucettinibs (>3–10 μM on DYRK1A), named iso-Leucettinibs, were synthesized and characterized as suitable negative control compounds for functional experiments. Leucettinibs, but not iso-Leucettinibs, inhibit the phosphorylation of DYRK1A substrates in cells. Leucettinibs provide new research tools and potential leads for further optimization toward therapeutic drug candidates.

更新日期：2023-07-24

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南