Manros Therapeutics & Perha Pharmaceuticals, Perharidy Research Center, 29680 Roscoff, Bretagne, France.
CNRS, 'Protein Phosphorylation and Human Disease' Group, Station Biologique De Roscoff, Place G. Teissier, Bp 74, 29682 Roscoff, Bretagne, France.
J Med Chem. 2022 Jan 27;65(2):1396-1417. doi: 10.1021/acs.jmedchem.1c01141. Epub 2021 Dec 20.
The protein kinase DYRK1A is involved in Alzheimer's disease, Down syndrome, diabetes, viral infections, and leukemia. Leucettines, a family of 2-aminoimidazolin-4-ones derived from the marine sponge alkaloid Leucettamine B, have been developed as pharmacological inhibitors of DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases). We report here on the synthesis and structure-activity relationship (SAR) of 68 Leucettines. Leucettines were tested on 11 purified kinases and in 5 cellular assays: (1) CLK1 pre-mRNA splicing, (2) Threonine-212-Tau phosphorylation, (3) glutamate-induced cell death, (4) autophagy and (5) antagonism of ligand-activated cannabinoid receptor CB1. The Leucettine SAR observed for DYRK1A is essentially identical for CLK1, CLK4, DYRK1B, and DYRK2. DYRK3 and CLK3 are less sensitive to Leucettines. In contrast, the cellular SAR highlights correlations between inhibition of specific kinase targets and some but not all cellular effects. Leucettines deserve further development as potential therapeutics against various diseases on the basis of their molecular targets and cellular effects.
蛋白激酶 DYRK1A 与阿尔茨海默病、唐氏综合征、糖尿病、病毒感染和白血病有关。亮菌素是一组来源于海洋海绵生物碱 Leucettamine B 的 2-氨基咪唑啉-4-ones，已被开发为 DYRKs（双特异性，酪氨酸磷酸化调节激酶）和 CLKs（cdc2 样激酶）的药理学抑制剂。我们在此报告了 68 种亮菌素的合成和结构-活性关系 (SAR)。亮菌素在 11 种纯化激酶和 5 种细胞测定中进行了测试：（1）CLK1 前 mRNA 剪接，（2）苏氨酸-212-Tau 磷酸化，（3）谷氨酸诱导的细胞死亡，（4）自噬和（5）配体激活大麻素受体 CB1 的拮抗作用。观察到的 DYRK1A 的亮菌素 SAR 对 CLK1、CLK4、DYRK1B 和 DYRK2 基本相同。DYRK3 和 CLK3 对亮菌素的敏感性较低。相比之下，细胞 SAR 突出了抑制特定激酶靶标与某些但不是所有细胞效应之间的相关性。亮菌素因其分子靶标和细胞效应而值得进一步开发，作为针对各种疾病的潜在治疗药物。
