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‐(α‐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.

[1]  M. Loh,et al.  JAK mutations in high-risk childhood acute lymphoblastic leukemia , 2009, Proceedings of the National Academy of Sciences.

[2]  Ashot Harutyunyan,et al.  A common JAK2 haplotype confers susceptibility to myeloproliferative neoplasms , 2009, Nature Genetics.

[3]  Andrew Collins,et al.  JAK2 haplotype is a major risk factor for the development of myeloproliferative neoplasms , 2009, Nature Genetics.

[4]  R. Levine,et al.  Janus kinase mutations. , 2009, Seminars in oncology.

[5]  Kenneth Offit,et al.  A germline JAK2 SNP is associated with predisposition to the development of JAK2V617F-positive myeloproliferative neoplasms , 2009, Nature Genetics.

[6]  Young Soon Kim,et al.  Biosynthesis and biotechnological production of serotonin derivatives , 2009, Applied Microbiology and Biotechnology.

[7]  A. Baruchel,et al.  Activating mutations in human acute megakaryoblastic leukemia. , 2008, Blood.

[8]  S. Constantinescu,et al.  Aberrant signal transduction pathways in myeloproliferative neoplasms , 2008, Leukemia.

[9]  Byung Hak Kim,et al.  A small-molecule compound identified through a cell-based screening inhibits JAK/STAT pathway signaling in human cancer cells , 2008, Molecular Cancer Therapeutics.

[10]  H. Kanegane,et al.  Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome , 2008, British journal of haematology.

[11]  J. O’Shea,et al.  Therapeutic targeting of Janus kinases , 2008, Immunological reviews.

[12]  E. Clappier,et al.  Somatically acquired JAK1 mutations in adult acute lymphoblastic leukemia , 2008, The Journal of experimental medicine.

[13]  H. Rui,et al.  Coactivation of janus tyrosine kinase (Jak)1 positively modulates prolactin-Jak2 signaling in breast cancer: recruitment of ERK and signal transducer and activator of transcription (Stat)3 and enhancement of Akt and Stat5a/b pathways. , 2007, Molecular endocrinology.

[14]  D. Levy,et al.  JAK-STAT Signaling: From Interferons to Cytokines* , 2007, Journal of Biological Chemistry.

[15]  D. Schuppan,et al.  Herbal medicine in the treatment of liver diseases. , 2007, Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver.

[16]  T. Naoe,et al.  JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults , 2007, Leukemia.

[17]  A. Yen,et al.  Inhibition of the janus kinase family increases extracellular signal-regulated kinase 1/2 phosphorylation and causes endoreduplication. , 2006, Cancer research.

[18]  M. Zeidler,et al.  JAK/STAT signalling in Drosophila: insights into conserved regulatory and cellular functions , 2006, Development.

[19]  Sandra A. Moore,et al.  Activating alleles of JAK3 in acute megakaryoblastic leukemia. , 2006, Cancer cell.

[20]  L. Klampfer,et al.  Signal transducers and activators of transcription (STATs): Novel targets of chemopreventive and chemotherapeutic drugs. , 2006, Current cancer drug targets.

[21]  Alan Cantor,et al.  Activation of Stat3 in Primary Tumors from High-Risk Breast Cancer Patients Is Associated with Elevated Levels of Activated Src and Survivin Expression , 2006, Clinical Cancer Research.

[22]  Zhong Zuo,et al.  Danshen: An Overview of Its Chemistry, Pharmacology, Pharmacokinetics, and Clinical Use , 2005, Journal of clinical pharmacology.

[23]  N. Perrimon,et al.  A genome-wide RNA interference screen in Drosophila melanogaster cells for new components of the Hh signaling pathway , 2005, Nature Genetics.

[24]  M. Loh,et al.  The JAK2V617F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia, but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia. , 2005, Blood.

[25]  J. Dimmock,et al.  The Mannich Base NC1153 Promotes Long-Term Allograft Survival and Spares the Recipient from Multiple Toxicities1 , 2005, The Journal of Immunology.

[26]  Norbert Perrimon,et al.  Genome-wide RNAi analysis of JAK/STAT signaling components in Drosophila. , 2005, Genes & development.

[27]  J. Darnell,et al.  Validating Stat3 in cancer therapy , 2005, Nature Medicine.

[28]  Stefan N. Constantinescu,et al.  A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera , 2005, Nature.

[29]  P. Campbell,et al.  Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders , 2005, The Lancet.

[30]  L. Notarangelo,et al.  Jak3, severe combined immunodeficiency, and a new class of immunosuppressive drugs , 2005, Immunological reviews.

[31]  Jae-Kwan Hwang,et al.  Inhibitory effects of active compounds isolated from safflower (Carthamus tinctorius L.) seeds for melanogenesis. , 2004, Biological & pharmaceutical bulletin.

[32]  J. Parsons,et al.  Src family kinases, key regulators of signal transduction , 2004, Oncogene.

[33]  Gerhard Eisenbrand,et al.  Molecular mechanisms of indirubin and its derivatives: novel anticancer molecules with their origin in traditional Chinese phytomedicine , 2004, Journal of Cancer Research and Clinical Oncology.

[34]  J. O’Shea,et al.  A new modality for immunosuppression: targeting the JAK/STAT pathway , 2004, Nature Reviews Drug Discovery.

[35]  J. Grover,et al.  Pharmacological actions and potential uses of Momordica charantia: a review. , 2004, Journal of ethnopharmacology.

[36]  F. E. Bertrand,et al.  JAK/STAT, Raf/MEK/ERK, PI3K/Akt and BCR-ABL in cell cycle progression and leukemogenesis , 2004, Leukemia.

[37]  Hua Yu,et al.  The STATs of cancer — new molecular targets come of age , 2004, Nature Reviews Cancer.

[38]  Norbert Perrimon,et al.  A sensitized genetic screen to identify novel regulators and components of the Drosophila janus kinase/signal transducer and activator of transcription pathway. , 2003, Genetics.

[39]  J. O’Shea,et al.  Prevention of Organ Allograft Rejection by a Specific Janus Kinase 3 Inhibitor , 2003, Science.

[40]  N. Perrimon,et al.  The Jak/STAT pathway in model organisms: emerging roles in cell movement. , 2002, Developmental cell.

[41]  J. Darnell,et al.  Signalling: STATs: transcriptional control and biological impact , 2002, Nature Reviews Molecular Cell Biology.

[42]  D. Frank,et al.  The role of STATs in apoptosis. , 2002, Current molecular medicine.

[43]  N. Schoene,et al.  Synthesis and characterization of N-coumaroyltyramine as a potent phytochemical which arrests human transformed cells via inhibiting protein tyrosine kinases. , 2002, Biochemical and biophysical research communications.

[44]  Z. Nagy,et al.  Selective inhibitor of Janus tyrosine kinase 3, PNU156804, prolongs allograft survival and acts synergistically with cyclosporine but additively with rapamycin. , 2002, Blood.

[45]  J. Pober,et al.  Interleukin-11 Up-Regulates Survivin Expression in Endothelial Cells through a Signal Transducer and Activator of Transcription-3 Pathway , 2001, Laboratory Investigation.

[46]  J. Turkson,et al.  Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. , 2001, The Journal of clinical investigation.

[47]  N. Perrimon,et al.  The roles of the Drosophila JAK/STAT pathway , 2000, Oncogene.

[48]  S. Muller,et al.  Inhibition of Caspase-3-mediated Poly(ADP-ribose) Polymerase (PARP) Apoptotic Cleavage by Human PARP Autoantibodies and Effect on Cells Undergoing Apoptosis* , 2000, The Journal of Biological Chemistry.

[49]  A. Shimizu,et al.  cis-N-(p-Coumaroyl)serotonin from Konnyaku, Amorphophallus konjac K. Koch , 2000, Bioscience, biotechnology, and biochemistry.

[50]  X. P. Liu,et al.  Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[51]  K. Onozaki,et al.  Serotonin derivative, N-(p-Coumaroyl)serotonin, isolated from safflower (Carthamus tinctorius L.) oil cake augments the proliferation of normal human and mouse fibroblasts in synergy with basic fibroblast growth factor (bFGF) or epidermal growth factor (EGF). , 1999, Journal of biochemistry.

[52]  K. Onozaki,et al.  Serotonin Derivative, N-(p-Coumaroyl) Serotonin, Inhibits the Production of TNF-α, IL-1α, IL-1β, and IL-6 by Endotoxin-Stimulated Human Blood Monocytes , 1998 .

[53]  A. Cumano,et al.  Jak2 Deficiency Defines an EssentialDevelopmental Checkpoint in DefinitiveHematopoiesis , 1998, Cell.

[54]  R. Schreiber,et al.  Targeted Disruption of the Stat1 Gene in Mice Reveals Unexpected Physiologic Specificity in the JAK–STAT Signaling Pathway , 1996, Cell.

[55]  H. Nakauchi,et al.  Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. , 1995, Immunity.

[56]  A. Sharpe,et al.  Defects in B Lymphocyte Maturation and T Lymphocyte Activation in Mice Lacking Jak3 , 1995, Science.

[57]  P. Doherty,et al.  Defective Lymphoid Development in Mice Lacking Jak3 , 1995, Science.

[58]  W. Farrar,et al.  Identification of interleukin-2 receptor-associated tyrosine kinase p116 as novel leukocyte-specific Janus kinase. , 1994, The Journal of biological chemistry.

[59]  J. Darnell,et al.  Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions , 1994, Cell.

[60]  W. Farrar,et al.  Activation of receptor-associated tyrosine kinase JAK2 by prolactin. , 1994, The Journal of biological chemistry.

[61]  Andrew Ziemiecki,et al.  Polypeptide signalling to the nucleus through tyrosine phosphorylation of Jak and Stat proteins , 1993, Nature.

[62]  G. Stark,et al.  Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-& gamma; signal transduction pathway , 1993, Nature.

[63]  J. Darnell,et al.  A single phosphotyrosine residue of Stat91 required for gene activation by interferon-gamma. , 1993, Science.

[64]  J. Darnell,et al.  Activation of transcription by IFN-gamma: tyrosine phosphorylation of a 91-kD DNA binding protein. , 1992, Science.

[65]  J. Darnell,et al.  Interferon-dependent tyrosine phosphorylation of a latent cytoplasmic transcription factor. , 1992, Science.

[66]  M. Fellous,et al.  A protein tyrosine kinase in the interferon α β signaling pathway , 1992, Cell.

[67]  M. Loh,et al.  The JAK 2 V 617 F activating mutation occurs in chronic myelomonocytic leukemia and acute myeloid leukemia , but not in acute lymphoblastic leukemia or chronic lymphocytic leukemia , 2005 .

[68]  B. Chilton,et al.  Prolactin and growth hormone signaling. , 2005, Current topics in developmental biology.

[69]  K. Onozaki,et al.  Serotonin derivative, N-(p-coumaroyl) serotonin, inhibits the production of TNF-alpha, IL-1alpha, IL-1beta, and IL-6 by endotoxin-stimulated human blood monocytes. , 1998, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[70]  G. Stark,et al.  A protein tyrosine kinase in the interferon alpha/beta signaling pathway. , 1992, Cell.