Perha Pharmaceuticals, Perharidy, 29680 Roscoff, France.
Edelris, Bâtiment Bioserra 1, 60 Avenue Rockefeller, 69008 Lyon, France.
J Med Chem. 2023 Aug 10;66(15):10694-10714. doi: 10.1021/acs.jmedchem.3c00884. Epub 2023 Jul 24.
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 2-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 2-substituted 2-aminoimidazolin-4-ones bearing a benzothiazol-6-ylmethylene, collectively named Leucettinibs, were synthesized and extensively characterized. Subnanomolar IC (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.
双特异性酪氨酸磷酸化调节激酶（DYRKs）和细胞分裂周期蛋白样激酶（CLKs）最近因其在各种病理过程中的核心作用而受到关注。我们在这里描述了一类来源于 Leucettines 和海洋天然产物 Leucettamine B 的 DYRK/CLK 抑制剂。合成了 45 种带有融合[6 + 5]-杂芳基亚甲基的 2-功能化 2-氨基咪唑啉-4-酮。在 15 种不同杂芳基亚甲基中，苯并噻唑-6-亚甲基被选为最有效的残基。合成并广泛表征了 186 种带有苯并噻唑-6-亚甲基的 2-取代 2-氨基咪唑啉-4-酮，统称为 Leucettinibs。鉴定出了纳摩尔级别的 IC（0.5-20 nM 对 DYRK1A）抑制剂，其中一种 Leucettinib 在 DYRK1A 中进行了建模，并与 CLK1 和抑制较弱的非靶点 CSNK2A1 共结晶。Leucettinib 的激酶失活异构体（对 DYRK1A 的>3-10 μM），命名为 iso-Leucettinibs，被合成并作为功能实验的合适阴性对照化合物进行了表征。Leucettinibs 而不是 iso-Leucettinibs，可抑制细胞中 DYRK1A 底物的磷酸化。Leucettinibs 为进一步优化治疗候选药物提供了新的研究工具和潜在先导化合物。
