MS-1020 is a novel small molecule that selectively inhibits JAK3 activity.

Abstract

In order to identify Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling inhibitors, a cell-based high throughput screening was performed using a plant extract library that identified Nb-(alpha-hydroxynaphthoyl)serotonin called MS-1020 as a novel JAK3 inhibitor. MS-1020 potently inhibited persistently-active STAT3 in a cell type-specific manner. Further examination showed that MS-1020 selectively blocked constitutively-active JAK3 and consistently suppressed interleukin-2-induced JAK3/STAT5 signalling but not prolactin-induced JAK2/STAT5 signalling. Furthermore, MS-1020 affected cell viability only in cancer cells harbouring persistently-active JAK3/STATs, and in vitro kinase assays showed MS-1020 binds directly with JAK3, blocking its catalytic activity. Therefore, the present study suggested that this reagent selectively inhibits JAK3 and subsequently leads to a block in STAT signalling. Finally, MS-1020 decreased cell survival by inducing apoptosis via down-regulation of anti-apoptotic gene expression. These results suggest that MS-1020 may have therapeutic potential in the treatment of cancers harbouring aberrant JAK3 signalling.

• Authors: Byung-Hak Kim, Sei-Ryang Oh, Chang-Hong Yin, Sangku Lee, Eun-Ah Kim, Min-Seok Kim, Claudio Sandoval, Somasundaram Jayabose, Erika A Bach, Hyeong-Kyu Lee, Gyeong-Hun Baeg
• Journal: British journal of haematology (Br J Haematol) Vol. 148 Issue 1 Pg. 132-43 (Jan 2010) ISSN: 1365-2141 [Electronic] England
• PMID: 19793252 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Interleukin-2
• Naphthols
• Nb-(alpha-hydroxynaphthoyl)serotonin
• Plant Extracts
• Protein Kinase Inhibitors
• STAT Transcription Factors
• STAT3 Transcription Factor
• STAT3 protein, human
• Serotonin
• Janus Kinase 3

Topics

• Animals
• Apoptosis (drug effects)
• Breast Neoplasms (metabolism, pathology)
• Cell Line
• Cell Survival (drug effects)
• Chromatography, High Pressure Liquid (methods)
• Dose-Response Relationship, Drug
• Drosophila
• Drug Screening Assays, Antitumor (methods)
• Hodgkin Disease (metabolism, pathology)
• Humans
• Interleukin-2 (pharmacology)
• Janus Kinase 3 (antagonists & inhibitors, metabolism)
• Naphthols (pharmacology)
• Plant Extracts (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Rats
• STAT Transcription Factors
• STAT3 Transcription Factor (metabolism)
• Serotonin (analogs & derivatives, pharmacology)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects)
• Tumor Cells, Cultured