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10-碘-11H-吲哚并[3,2-c]喹啉-6-羧酸是双重特异性酪氨酸磷酸酶样激酶1A（DYRK1A）的选择性抑制剂。

10-iodo-11H-indolo[3,2-c]quinoline-6-carboxylic acids are selective inhibitors of DYRK1A.

作者信息

Falke Hannes, Chaikuad Apirat, Becker Anja, Loaëc Nadège, Lozach Olivier, Abu Jhaisha Samira, Becker Walter, Jones Peter G, Preu Lutz, Baumann Knut, Knapp Stefan, Meijer Laurent, Kunick Conrad

机构信息

†Institut für Medizinische und Pharmazeutische Chemie, Technische Universität Braunschweig, Beethovenstraße 55, 38106 Braunschweig, Germany.

‡Nuffield Department of Clinical Medicine, Structural Genomics Consortium, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Headington, Oxford OX3 7DQ, U.K.

出版信息

J Med Chem. 2015 Apr 9;58(7):3131-43. doi: 10.1021/jm501994d. Epub 2015 Mar 23.

DOI:10.1021/jm501994d
PMID:25730262
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4506206/
Abstract

The protein kinase DYRK1A has been suggested to act as one of the intracellular regulators contributing to neurological alterations found in individuals with Down syndrome. For an assessment of the role of DYRK1A, selective synthetic inhibitors are valuable pharmacological tools. However, the DYRK1A inhibitors described in the literature so far either are not sufficiently selective or have not been tested against closely related kinases from the DYRK and the CLK protein kinase families. The aim of this study was the identification of DYRK1A inhibitors exhibiting selectivity versus the structurally and functionally closely related DYRK and CLK isoforms. Structure modification of the screening hit 11H-indolo[3,2-c]quinoline-6-carboxylic acid revealed structure-activity relationships for kinase inhibition and enabled the design of 10-iodo-substituted derivatives as very potent DYRK1A inhibitors with considerable selectivity against CLKs. X-ray structure determination of three 11H-indolo[3,2-c]quinoline-6-carboxylic acids cocrystallized with DYRK1A confirmed the predicted binding mode within the ATP binding site.

摘要

蛋白激酶DYRK1A被认为是导致唐氏综合征患者出现神经学改变的细胞内调节因子之一。为了评估DYRK1A的作用，选择性合成抑制剂是有价值的药理学工具。然而，迄今为止文献中描述的DYRK1A抑制剂要么选择性不足，要么未针对来自DYRK和CLK蛋白激酶家族的密切相关激酶进行测试。本研究的目的是鉴定对结构和功能密切相关的DYRK和CLK亚型具有选择性的DYRK1A抑制剂。筛选命中物11H-吲哚并[3,2-c]喹啉-6-羧酸的结构修饰揭示了激酶抑制的构效关系，并使得能够设计出10-碘取代衍生物作为非常有效的DYRK1A抑制剂，对CLKs具有相当的选择性。与DYRK1A共结晶的三种11H-吲哚并[3,2-c]喹啉-6-羧酸的X射线结构测定证实了ATP结合位点内预测的结合模式。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/cbeb717d30ff/jm-2014-01994d_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/c2cb5a334954/jm-2014-01994d_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/cca16610935e/jm-2014-01994d_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/eb34d54315e1/jm-2014-01994d_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/36fa0e44cfc1/jm-2014-01994d_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/ee45c5ac4fe8/jm-2014-01994d_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/284b7dbd63de/jm-2014-01994d_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/c6d17aea4560/jm-2014-01994d_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/cbeb717d30ff/jm-2014-01994d_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/c2cb5a334954/jm-2014-01994d_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/cca16610935e/jm-2014-01994d_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/eb34d54315e1/jm-2014-01994d_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/36fa0e44cfc1/jm-2014-01994d_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/ee45c5ac4fe8/jm-2014-01994d_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/284b7dbd63de/jm-2014-01994d_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/c6d17aea4560/jm-2014-01994d_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/81c7/4506206/cbeb717d30ff/jm-2014-01994d_0006.jpg

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