Novel Inverse Binding Mode of Indirubin Derivatives Yields Improved Selectivity for DYRK Kinases
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- 作者：Vassilios Myrianthopoulos ; Marina Kritsanida ; Nicolas Gaboriaud-Kolar ; Prokopios Magiatis ; Yoan Ferandin ; Emilie Durieu ; Olivier Lozach ; Daniel Cappel ; Meera Soundararajan ; Panagis Filippakopoulos ; Woody Sherman ; Stefan Knapp ; Laurent Meijer ; Emmanuel Mikros ; Alexios-Leandros Skaltsounis
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：January 10, 2013
- 年：2013
- 卷：4
- 期：1
- 页码：22-26
- 全文大小：230K
- 年卷期：v.4,no.1(January 10, 2013)
- ISSN：1948-5875
文摘
DYRK kinases are involved in alternative pre-mRNA splicing as well as in neuropathological states such as Alzheimer's disease and Down syndrome. In this study, we present the design, synthesis, and biological evaluation of indirubins as DYRK inhibitors with enhanced selectivity. Modifications of the bis-indole included polar or acidic functionalities at positions 5鈥?and 6鈥?and a bromine or a trifluoromethyl group at position 7, affording analogues that possess high activity and pronounced specificity. Compound 6i carrying a 5鈥?carboxylate moiety demonstrated the best inhibitory profile. A novel inverse binding mode, which forms the basis for the improved selectivity, was suggested by molecular modeling and confirmed by determining the crystal structure of DYRK2 in complex with 6i. Structure鈥揳ctivity relationships were further established, including a thermodynamic analysis of binding site water molecules, offering a structural explanation for the selective DYRK inhibition.