Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

Chiang, Chien‐Hung; Lin, Yu‐Hsiang; Lin, Shu Fu; Lai, Chun‐Liang; Liu, Chia-Wei; Wei, Win-Yin; Yang, Sheng-Chuan; Wang, Ruwen; Teng, Li-Wei; Chuang, Shuang‐En; Chang, Jia‐Ming; Yuan, Ta-Tung; Lee, Ying-Shuen; Chen, Paonien; Chi, Wei-Kuang; Yang, Ju‐Ying; Huang, Hsin-I; Liao, Chu‐Bin; Huang, Jow Lay

doi:10.1021/jm1001869

Cited by 60 publications

(38 citation statements)

References 35 publications

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“…The GI 50 values in HeLa cells were 96 ± 5 nM ( MLN-1 ), 182 ± 9 nM ( MLN-2 ), and 844 ± 23 nM ( MLN-3 ), while MLN8237 showed a GI 50 value of 72 ± 5 nM. To further investigate the relative potency of MLN-1/2/3 in inhibiting endogenous AKA activities, we tested their effects on cellular phosphorylation of histone H3 at serine 10 36 . As shown in Figure 2B , both MLN8237 and MLN-1 completely suppressed histone H3 phosphorylation at 1 μM, while the same effect was achieved with 10 μM of MLN-2 .…”

Section: Resultsmentioning

confidence: 99%

Multiplex Imaging and Cellular Target Identification of Kinase Inhibitors via an Affinity-Based Proteome Profiling Approach

Pan

et al. 2015

Sci Rep

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MLN8237 is a highly potent and presumably selective inhibitor of Aurora kinase A (AKA) and has shown promising antitumor activities. Like other kinase inhibitors which target the ATP-binding site of kinases, MLN8237 might be expected to have potential cellular off-targets. Herein, we report the first photoaffinity-based, small molecule AKA probe capable of both live-cell imaging of AKA activities and in situ proteome profiling of potential off-targets of MLN8237 (including AKA-associating proteins). By using two mutually compatible, bioorthogonal reactions (copper-catalyzed azide-alkyne cycloaddition chemistry and TCO-tetrazine ligation), we demostrate small molecule-based multiplex bioimaging for simultaneous in situ monitoring of two important cell-cycle regulating kinases (AKA and CDK1). A broad range of proteins, as potential off-targets of MLN8237 and AKA's-interacting partners, is subsequently identified by affinity-based proteome profiling coupled with large-scale LC-MS/MS analysis. From these studies, we discover novel AKA interactions which were further validated by cell-based immunoprecipitation (IP) experiments.

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Section: Resultsmentioning

confidence: 99%

Multiplex Imaging and Cellular Target Identification of Kinase Inhibitors via an Affinity-Based Proteome Profiling Approach

Pan

et al. 2015

Sci Rep

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“…All of the 35 compounds and associated data involved in this study were obtained from literature [13]. The inhibitory activity data were reported as IC 50 against Aurora A.…”

Section: Methodsmentioning

confidence: 99%

“…A series of pyrrole-indoline-2-ones with Aurora A inhibitory activities were reported [13]. These pyrrole-indoline-2-ones, with excellent Aurora A inhibitory activities, were designed and synthesized by sharing a similar scaffold with Hesperadin [14].…”

Section: Introductionmentioning

confidence: 99%

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Wang

Sun

et al. 2011

IJMS

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Aurora kinases have emerged as attractive targets for the design of anticancer drugs. 3D-QSAR (comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)) and Surflex-docking studies were performed on a series of pyrrole-indoline-2-ones as Aurora A inhibitors. The CoMFA and CoMSIA models using 25 inhibitors in the training set gave r2cv values of 0.726 and 0.566, and r2 values of 0.972 and 0.984, respectively. The adapted alignment method with the suitable parameters resulted in reliable models. The contour maps produced by the CoMFA and CoMSIA models were employed to rationalize the key structural requirements responsible for the activity. Surflex-docking studies revealed that the sulfo group, secondary amine group on indolin-2-one, and carbonyl of 6,7-dihydro-1H-indol-4(5H)-one groups were significant for binding to the receptor, and some essential features were also identified. Based on the 3D-QSAR and docking results, a set of new molecules with high predicted activities were designed.

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“…Overexpression of Aurora-A has been shown to lead to centrosome amplification and aneuploidy, which usually results from incomplete cytokinesis and can be a driving force in genomic instability and tumorigenesis [99]. Chiang et al [100] reported the synthesis of a series of new 5-substituted pyrrole-indolin-2-one derivatives and tested their inhibition profile for Aurora kinases. They identified two compounds with potent inhibition profile towards Aurora kinase A and B.…”

Section: Aurora Kinase Inhibitormentioning

confidence: 99%

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

Prakash¹,

Raja

2012

MRMC

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Kinases are probably the most important signaling enzymes, which represent about 20% of the druggable genome. Currently, more than 150 kinases are known. So, kinase inhibition therapy has become a very important area of drug research since most of our diseases are related to intra or intercellular signaling by kinases. Indole alkaloids are extensively studied for their biological activities in several pharmaceutical areas, including, for example, antitumor. Among this chemical family, indolinone displays very promising antitumor properties by inhibiting various kinase families. These small molecules have a low molecular weight and most of them bind to protein kinases competing with ATP for the ATP-binding site. This review focuses on the indolinone based drugs approved for the treatment of cancer, drugs under clinical trial and then chemical diversity of various synthetic analogues of indolinone and their metabolites as various kinase inhibitors. This review also focused on structural activity relationship (SAR), mechanisms of action and biological targets through which indolinone and its derivatives display their antitumor activity.

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Discovery of Pyrrole−Indoline-2-ones as Aurora Kinase Inhibitors with a Different Inhibition Profile

Cited by 60 publications

References 35 publications

Multiplex Imaging and Cellular Target Identification of Kinase Inhibitors via an Affinity-Based Proteome Profiling Approach

Multiplex Imaging and Cellular Target Identification of Kinase Inhibitors via an Affinity-Based Proteome Profiling Approach

Combined 3D-QSAR Modeling and Molecular Docking Studies on Pyrrole-Indolin-2-ones as Aurora A Kinase Inhibitors

Indolinones as Promising Scaffold as Kinase Inhibitors: A Review

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