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Molecules 2017, 22(9), 1546; doi:10.3390/molecules22091546

Methylisoindigo and Its Bromo-Derivatives Are Selective Tyrosine Kinase Inhibitors, Repressing Cellular Stat3 Activity, and Target CD133+ Cancer Stem Cells in PDAC

1
Department of Pharmacy and Molecular Biotechnology, Division of Pharmaceutical Biology, University of Heidelberg, Im Neuenheimer Feld 364, D-69120 Heidelberg, Germany
2
Department of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Erwin-Schrödinger-Strasse 52, D-67663 Kaiserslautern, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 7 August 2017 / Revised: 11 September 2017 / Accepted: 11 September 2017 / Published: 13 September 2017
(This article belongs to the Special Issue Kinase Inhibitors)
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Abstract

Indirubin is an active component of the herbal ingredient ‘Danggui Longhui wan’, which was used for the treatment of inflammation and chronic myeloid leukemia in China. The recent study showed its derivative methylisoindigo (also known as meisoindigo) preferentially targeting cancer stem cells (CSCs) in interference with AMPK and LKB1, the cellular metabolic sensors. In this study, we screened the effect of meisoindigo on a panel of 300 protein kinases and found that it selectively inhibited Stat3-associated tyrosine kinases and further confirmed its activity in cell based assays. To gain a deeper insight into the structure–activity relationship we produced 7 bromo-derivatives exhausting the accessible positions on the bisindole backbone except for in the 4-position due to the space limitation. We compared their anti-proliferative effects on tumor cells. We found that 6-bromomeisoindigo showed improved toxicity in company with increased Stat3 inhibition. Moreover, we detected that 6-bromomeisoindigo induced apoptosis of 95% of CD133+ pancreatic cancer cells. Considering that CD133 is a common marker highly expressed in a range of CSCs, our results imply the potential application of 6-bromomeisoindigo for the treatment of CSCs in different types of cancers. View Full-Text
Keywords: indirubin; meisoindigo; cancer stem cells; Stat3 inhibitor; selective protein kinase inhibitor; TCM; structure-activity-relationship indirubin; meisoindigo; cancer stem cells; Stat3 inhibitor; selective protein kinase inhibitor; TCM; structure-activity-relationship
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Tegethoff, J.; Bischoff, R.; Saleh, S.; Blagojevic, B.; Merz, K.-H.; Cheng, X. Methylisoindigo and Its Bromo-Derivatives Are Selective Tyrosine Kinase Inhibitors, Repressing Cellular Stat3 Activity, and Target CD133+ Cancer Stem Cells in PDAC. Molecules 2017, 22, 1546.

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