MS-1020 is a novel small molecule that selectively inhibits JAK3 activity.
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.
Pediatrics-Hematology/Oncology, New York Medical College, Valhalla, NY, USA.
Byung-Hak
BH
Kim
Sei-Ryang
SR
Oh
Chang-Hong
CH
Yin
Sangku
S
Lee
Eun-Ah
EA
Kim
Min-Seok
MS
Kim
Claudio
C
Sandoval
Somasundaram
S
Jayabose
Erika A
EA
Bach
Hyeong-Kyu
HK
Lee
Gyeong-Hun
GH
Baeg
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D004305:Dose-Response Relationship, Drug; D004330:Drosophila; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006689:Hodgkin Disease / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009284:Naphthols / Q000494:pharmacology*; D010936:Plant Extracts / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012701:Serotonin / Q000031:analogs & derivatives* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D014407:Tumor Cells, Cultured
D007376:Interleukin-2; D009284:Naphthols; C548376:Nb-(alpha-hydroxynaphthoyl)serotonin; D010936:Plant Extracts; D047428:Protein Kinase Inhibitors; D050791:STAT Transcription Factors; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D012701:Serotonin; D053616:Janus Kinase 3