Tubulosine selectively inhibits JAK3 signalling by binding to the ATP-binding site of the kinase of JAK3.
Adenosine Triphosphate
/ metabolism
Apoptosis
/ drug effects
Autophagy
/ drug effects
Binding Sites
Cell Line, Tumor
Cell Proliferation
/ drug effects
Cell Survival
/ drug effects
Emetine
/ analogs & derivatives
Humans
Janus Kinase 3
/ antagonists & inhibitors
Models, Biological
Necrosis
Oncogenes
STAT5 Transcription Factor
/ metabolism
Signal Transduction
/ drug effects
JAK3
STAT
leukaemia
lymphoma
structure-based computational database screening
tubulosine
Journal
Journal of cellular and molecular medicine
ISSN: 1582-4934
Titre abrégé: J Cell Mol Med
Pays: England
ID NLM: 101083777
Informations de publication
Date de publication:
07 2020
07 2020
Historique:
received:
11
06
2019
revised:
15
08
2019
accepted:
22
08
2019
pubmed:
20
6
2020
medline:
29
4
2021
entrez:
20
6
2020
Statut:
ppublish
Résumé
Gain- or loss-of-function mutations in Janus kinase 3 (JAK3) contribute to the pathogenesis of various haematopoietic malignancies and immune disorders, suggesting that aberrant JAK3 signalling is an attractive therapeutic target to treat these disorders. In this study, we performed structure-based computational database screening using the 3D structure of the JAK3 kinase domain and the National Cancer Institute diversity set and identified tubulosine as a novel JAK3 inhibitor. Tubulosine directly blocked the catalytic activity of JAK3 by selective interacting with the JAK3 kinase domain. Consistently, tubulosine potently inhibited persistently activated and interleukin-2-dependent JAK3, and JAK3-mediated downstream targets. Importantly, it did not affect the activity of other JAK family members, particularly prolactin-induced JAK2/signal transducer and activator of transcription 5 and interferon alpha-induced JAK1-TYK2/STAT1. Tubulosine specifically decreased survival and proliferation of cancer cells, in which persistently active JAK3 is expressed, by inducing apoptotic and necrotic/autophagic cell death without affecting other oncogenic signalling. Collectively, tubulosine is a potential small-molecule compound that selectively inhibits JAK3 activity, suggesting that it may serve as a promising therapeutic candidate for treating disorders caused by aberrant activation of JAK3 signalling.
Identifiants
pubmed: 32558259
doi: 10.1111/jcmm.15362
pmc: PMC7339168
doi:
Substances chimiques
STAT5 Transcription Factor
0
tubulosine
2632-29-3
Adenosine Triphosphate
8L70Q75FXE
Janus Kinase 3
EC 2.7.10.2
Emetine
X8D5EPO80M
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
7427-7438Informations de copyright
© 2020 The Authors. Journal of Cellular and Molecular Medicine. published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.
Références
Int Immunol. 2000 Feb;12(2):123-32
pubmed: 10653847
J Comput Chem. 2009 Dec;30(16):2785-91
pubmed: 19399780
Blood. 2005 Aug 1;106(3):996-1002
pubmed: 15831699
Nature. 1995 Sep 7;377(6544):65-8
pubmed: 7659163
Leukemia. 2012 Sep;26(9):2144-6
pubmed: 22425895
Eur J Biochem. 1976 Apr 15;64(1):1-5
pubmed: 776609
Curr Top Med Chem. 2014;14(16):1923-38
pubmed: 25262799
Blood. 2006 Jan 1;107(1):176-83
pubmed: 16174768
EMBO J. 2000 Nov 1;19(21):5720-8
pubmed: 11060023
Science. 1991 Jul 5;253(5015):77-9
pubmed: 2063207
Blood. 2009 Mar 19;113(12):2746-54
pubmed: 19139084
J Comput Chem. 2005 Dec;26(16):1668-88
pubmed: 16200636
J Nat Prod. 1990 Jul-Aug;53(4):1009-14
pubmed: 1982768
J Mol Biol. 2009 Mar 20;387(1):219-32
pubmed: 19361440
Curr Top Med Chem. 2004;4(7):687-700
pubmed: 15032682
Arch Pathol Lab Med. 2005 Aug;129(8):990-6
pubmed: 16048411
Br J Haematol. 2010 Jan;148(1):132-43
pubmed: 19793252
Nature. 2003 May 22;423(6938):452-6
pubmed: 12761551
Leuk Res. 2007 Feb;31(2):203-9
pubmed: 16790275
Curr Drug Targets. 2018;19(5):487-500
pubmed: 27928945
Blood. 2000 Mar 15;95(6):2076-83
pubmed: 10706877
Science. 1995 Nov 3;270(5237):800-2
pubmed: 7481769
Nucleic Acids Res. 2007 Jul;35(Web Server issue):W522-5
pubmed: 17488841
J Nat Prod. 1999 Sep;62(9):1346-8
pubmed: 10514334
Leukemia. 2011 Aug;25(8):1365-8
pubmed: 21537335
Blood. 2009 Feb 12;113(7):1483-92
pubmed: 19047679
J Clin Invest. 2010 Jun;120(6):2131-43
pubmed: 20440074
Front Immunol. 2018 Mar 20;9:563
pubmed: 29662489
Curr Drug Targets. 2011 Apr;12(4):546-55
pubmed: 21126226
Leukemia. 2007 Mar;21(3):574-6
pubmed: 17252020
Cell Death Differ. 2011 Apr;18(4):571-80
pubmed: 21311563
Cell Immunol. 2001 Aug 1;211(2):131-42
pubmed: 11591117
J Breast Cancer. 2019 Aug 02;22(3):362-374
pubmed: 31598337
Hum Pathol. 2005 Sep;36(9):939-44
pubmed: 16153455
Nat Rev Immunol. 2009 Jul;9(7):480-90
pubmed: 19543225
Cell. 2012 Jul 20;150(2):339-50
pubmed: 22817896
Mol Pharmacol. 2015 Apr;87(4):572-81
pubmed: 25583084
Biochem J. 2014 Aug 15;462(1):1-13
pubmed: 25057888
Annu Rev Med. 2015;66:311-28
pubmed: 25587654
J Cell Mol Med. 2020 Jul;24(13):7427-7438
pubmed: 32558259
J Mol Biol. 2010 Jul 16;400(3):413-33
pubmed: 20478313
Pharmacol Res. 2016 Sep;111:784-803
pubmed: 27473820
Leuk Lymphoma. 2015 May;56(5):1502-6
pubmed: 25146434
J Biol Chem. 1994 Jul 22;269(29):19136-41
pubmed: 7518451
Blood Cancer J. 2011 Dec;1(12):e46
pubmed: 22829094
Planta Med. 2008 Feb;74(3):258-63
pubmed: 18302092
Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9414-8
pubmed: 19470474
Leukemia. 2001 Dec;15(12):1923-31
pubmed: 11753614
Science. 1967 Jul 7;157(3784):84-5
pubmed: 4381747
Science. 1995 Nov 3;270(5237):797-800
pubmed: 7481768
Cancer Cell. 2006 Jul;10(1):65-75
pubmed: 16843266
Exp Dermatol. 2015 Jul;24(7):503-9
pubmed: 25808463
Nat Rev Drug Discov. 2017 Dec;16(12):843-862
pubmed: 29104284
N Engl J Med. 2010 Jul 22;363(4):355-64
pubmed: 20660403