Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B

Tahtouh T.; Elkins J.M.; Filippakopoulos P.; Soundararajan M.; Burgy G.; Durieu E.; Cochet C.; Schmid R.S.; Lo D.C.; Delhommel F.; Oberholzer A.E.; Pearl L.H.; Carreaux F.; Bazureau J.-P.; Knapp S.; Meijer L.

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Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B

机译：亮氨酸的选择性，共晶结构和神经保护特性，亮氨酸是一种来自海洋海绵生物碱亮翠胺B的蛋白激酶抑制剂家族

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DYRKs (dual specificity, tyrosine phosphorylation regulated kinases) and CLKs (cdc2-like kinases) are implicated in the onset and development of Alzheimers disease and Down syndrome. The marine sponge alkaloid leucettamine B was recently identified as an inhibitor of DYRKs/CLKs. Synthesis of analogues (leucettines) led to an optimized product, leucettine L41. Leucettines were cocrystallized with DYRK1A, DYRK2, CLK3, PIM1, and GSK-3β. The selectivity of L41 was studied by activity and interaction assays of recombinant kinases and affinity chromatography and competition affinity assays. These approaches revealed unexpected potential secondary targets such as CK2, SLK, and the lipid kinase PIKfyve/Vac14/Fig4. L41 displayed neuroprotective effects on glutamate-induced HT22 cell death. L41 also reduced amyloid precursor protein-induced cell death in cultured rat brain slices. The unusual multitarget selectivity of leucettines may account for their neuroprotective effects. This family of kinase inhibitors deserves further optimization as potential therapeutics against neurodegenerative diseases such as Alzheimers disease.

机译：DYRKs（双重特异性，酪氨酸磷酸化调节激酶）和CLKs（cdc2样激酶）与阿尔茨海默氏病和唐氏综合症的发生和发展有关。最近鉴定出海洋海绵生物碱亮氨酰胺B是DYRKs / CLKs的抑制剂。合成类似物（亮氨酸）可以得到优化的产品，leucettine L41。亮氨酸与DYRK1A，DYRK2，CLK3，PIM1和GSK-3β共结晶。通过重组激酶的活性和相互作用测定，亲和层析和竞争亲和测定来研究L41的选择性。这些方法揭示了出乎意料的潜在二级目标，例如CK2，SLK和脂质激酶PIKfyve / Vac14 / Fig4。 L41对谷氨酸诱导的HT22细胞死亡显示出神经保护作用。 L41还减少了培养的大鼠脑切片中淀粉样蛋白前体蛋白诱导的细胞死亡。亮氨酸的不同寻常的多靶点选择性可能是其神经保护作用的原因。该激酶抑制剂家族作为针对神经退行性疾病例如阿尔茨海默氏病的潜在治疗剂值得进一步优化。

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《Journal of Medicinal Chemistry》 |2012年第21期|共19页
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Tahtouh T.; Elkins J.M.; Filippakopoulos P.; Soundararajan M.; Burgy G.; Durieu E.; Cochet C.; Schmid R.S.; Lo D.C.; Delhommel F.; Oberholzer A.E.; Pearl L.H.; Carreaux F.; Bazureau J.-P.; Knapp S.; Meijer L.;
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1. Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B [J] . Tahtouh T., Elkins J.M., Filippakopoulos P., Journal of Medicinal Chemistry . 2012,第21期

机译：亮氨酸的选择性，共晶结构和神经保护特性，亮氨酸是一种来自海洋海绵生物碱亮翠胺B的蛋白激酶抑制剂家族
2. Synthesis and preliminary biological evaluation of new derivatives of the marine alkaloid leucettamine B as kinase inhibitors. [J] . Debdab M, Renault S, Lozach O, European Journal of Medicinal Chemistry: Chimie Therapeutique . 2010,第2期

机译：海洋生物碱亮光胺B作为激酶抑制剂的新衍生物的合成和初步生物学评估。
3. Aldisine alkaloids from the Philippine sponge Stylissa massa are potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK-1). [J] . Tasdemir Deniz, Mallon Robert, Greenstein Michael, Journal of Medicinal Chemistry . 2002,第2期

机译：来自菲律宾海绵铁笔属的Aldisine生物碱是促分裂原活化蛋白激酶激酶1（MEK-1）的有效抑制剂。
4. CNX-774, an Irreversible, Selective and Orally Bioavailable Inhibitor of Bruton's Tyrosine Kinase: In Vitro ADME, Selectivity, and Pharmacokinetic Properties [C] . Prasoon Chaturvedi, Matthew Labenski, Erica Evans, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2011

机译：CNX-774，Bruton的酪氨酸激酶的不可逆转，选择性和口服生物可利用的抑制剂：体外Adme，选择性和药代动力学性能
5. Marine sponge-derived sipholane triterpenoids reverse P-glycoprotein (ABCB1)-mediated multidrug resistance in cancer cells [D] . Abraham, Ioana 2012

机译：海洋海绵衍生的七环素三萜类化合物逆转癌细胞中的P-糖蛋白（ABCB1）介导的多药耐药性
6. Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK CLK Kinases [O] . Nadège Loaëc, Eletta Attanasio, Benoît Villiers, 2017

机译：海洋衍生的2-氨基咪唑啉酮生物碱。 Leucettamine B相关的polyandrocarpamines抑制哺乳动物和原生动物的DYRK和CLK激酶。
7. Marine-Derived 2-Aminoimidazolone Alkaloids. Leucettamine B-Related Polyandrocarpamines Inhibit Mammalian and Protozoan DYRK & CLK Kinases [O] . Loaëc, Nadège, Attanasio, Eletta, Villiers, Benoît, 2017

机译：海洋衍生的2-氨基咪唑啉酮生物碱。 Leucettamine B相关的polyandrocarpamines抑制哺乳动物和原生动物的DYRK和CLK激酶。
8. Solution structure analysis of the conformational changes that occur upon the binding of the protein kinase inhibitor peptide to the catalytic subunit of the cAMP dependent protein kinase [R] . Mitchell, R. D. , Walsh, D. A. , Olah, G. A. , 1994

机译：蛋白激酶抑制剂肽与camp依赖性蛋白激酶催化亚基结合后发生的构象变化的溶液结构分析

Selectivity, cocrystal structures, and neuroprotective properties of leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid leucettamine B

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