| Structural highlights
Disease
JAK3_HUMAN Defects in JAK3 are a cause of severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-negative (T(-)B(+)NK(-) SCID) [MIM:600802. A form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.[1] [2] [3] [:][4] [5] [6] [7] [8]
Function
JAK3_HUMAN Non-receptor tyrosine kinase involved in various processes such as cell growth, development, or differentiation. Mediates essential signaling events in both innate and adaptive immunity and plays a crucial role in hematopoiesis during T-cells development. In the cytoplasm, plays a pivotal role in signal transduction via its association with type I receptors sharing the common subunit gamma such as IL2R, IL4R, IL7R, IL9R, IL15R and IL21R. Following ligand binding to cell surface receptors, phosphorylates specific tyrosine residues on the cytoplasmic tails of the receptor, creating docking sites for STATs proteins. Subsequently, phosphorylates the STATs proteins once they are recruited to the receptor. Phosphorylated STATs then form homodimer or heterodimers and translocate to the nucleus to activate gene transcription. For example, upon IL2R activation by IL2, JAK1 and JAK3 molecules bind to IL2R beta (IL2RB) and gamma chain (IL2RG) subunits inducing the tyrosine phosphorylation of both receptor subunits on their cytoplasmic domain. Then, STAT5A AND STAT5B are recruited, phosphorylated and activated by JAK1 and JAK3. Once activated, dimerized STAT5 translocates to the nucleus and promotes the transcription of specific target genes in a cytokine-specific fashion.[9] [10] [11]
Publication Abstract from PubMed
The Janus kinases (JAKs) and their downstream effectors, signal transducer and activator of transcription proteins (STATs), form a critical immune cell signaling circuit, which is of fundamental importance in innate immunity, inflammation, and hematopoiesis, and dysregulation is frequently observed in immune disease and cancer. The high degree of structural conservation of the JAK ATP binding pockets has posed a considerable challenge to medicinal chemists seeking to develop highly selective inhibitors as pharmacological probes and as clinical drugs. Here we report the discovery and optimization of 2,4-substituted pyrimidines as covalent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Investigation of structure-activity relationship (SAR) utilizing biochemical and transformed Ba/F3 cellular assays resulted in identification of potent and selective inhibitors such as compounds 9 and 45. A 2.9 A cocrystal structure of JAK3 in complex with 9 confirms the covalent interaction. Compound 9 exhibited decent pharmacokinetic properties and is suitable for use in vivo. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.
Development of Selective Covalent Janus Kinase 3 Inhibitors.,Tan L, Akahane K, McNally R, Reyskens KM, Ficarro SB, Liu S, Herter-Sprie GS, Koyama S, Pattison MJ, Labella K, Johannessen L, Akbay EA, Wong KK, Frank DA, Marto JA, Look TA, Arthur JS, Eck MJ, Gray NS J Med Chem. 2015 Aug 27;58(16):6589-606. doi: 10.1021/acs.jmedchem.5b00710. Epub , 2015 Aug 18. PMID:26258521[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kurzer JH, Argetsinger LS, Zhou YJ, Kouadio JL, O'Shea JJ, Carter-Su C. Tyrosine 813 is a site of JAK2 autophosphorylation critical for activation of JAK2 by SH2-B beta. Mol Cell Biol. 2004 May;24(10):4557-70. PMID:15121872
- ↑ Cheng H, Ross JA, Frost JA, Kirken RA. Phosphorylation of human Jak3 at tyrosines 904 and 939 positively regulates its activity. Mol Cell Biol. 2008 Apr;28(7):2271-82. doi: 10.1128/MCB.01789-07. Epub 2008 Feb, 4. PMID:18250158 doi:10.1128/MCB.01789-07
- ↑ Boggon TJ, Li Y, Manley PW, Eck MJ. Crystal structure of the Jak3 kinase domain in complex with a staurosporine analog. Blood. 2005 Aug 1;106(3):996-1002. Epub 2005 Apr 14. PMID:15831699 doi:http://dx.doi.org/10.1182/blood-2005-02-0707
- ↑ Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O'Shea JJ, et al.. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature. 1995 Sep 7;377(6544):65-8. PMID:7659163 doi:http://dx.doi.org/10.1038/377065a0
- ↑ Candotti F, Oakes SA, Johnston JA, Giliani S, Schumacher RF, Mella P, Fiorini M, Ugazio AG, Badolato R, Notarangelo LD, Bozzi F, Macchi P, Strina D, Vezzoni P, Blaese RM, O'Shea JJ, Villa A. Structural and functional basis for JAK3-deficient severe combined immunodeficiency. Blood. 1997 Nov 15;90(10):3996-4003. PMID:9354668
- ↑ Bozzi F, Lefranc G, Villa A, Badolato R, Schumacher RF, Khalil G, Loiselet J, Bresciani S, O'Shea JJ, Vezzoni P, Notarangelo LD, Candotti F. Molecular and biochemical characterization of JAK3 deficiency in a patient with severe combined immunodeficiency over 20 years after bone marrow transplantation: implications for treatment. Br J Haematol. 1998 Sep;102(5):1363-6. PMID:9753072
- ↑ Schumacher RF, Mella P, Badolato R, Fiorini M, Savoldi G, Giliani S, Villa A, Candotti F, Tampalini A, O'Shea JJ, Notarangelo LD. Complete genomic organization of the human JAK3 gene and mutation analysis in severe combined immunodeficiency by single-strand conformation polymorphism. Hum Genet. 2000 Jan;106(1):73-9. PMID:10982185
- ↑ Roberts JL, Lengi A, Brown SM, Chen M, Zhou YJ, O'Shea JJ, Buckley RH. Janus kinase 3 (JAK3) deficiency: clinical, immunologic, and molecular analyses of 10 patients and outcomes of stem cell transplantation. Blood. 2004 Mar 15;103(6):2009-18. Epub 2003 Nov 13. PMID:14615376 doi:10.1182/blood-2003-06-2104
- ↑ Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB, Shibuya K, Ortaldo JR, McVicar DW, O'Shea JJ. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature. 1994 Jul 14;370(6485):151-3. PMID:8022485 doi:http://dx.doi.org/10.1038/370151a0
- ↑ Sharfe N, Dadi HK, Roifman CM. JAK3 protein tyrosine kinase mediates interleukin-7-induced activation of phosphatidylinositol-3' kinase. Blood. 1995 Sep 15;86(6):2077-85. PMID:7662955
- ↑ Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B. IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. J Clin Invest. 2010 Jun;120(6):2131-43. doi: 10.1172/JCI41344. Epub 2010 May 3. PMID:20440074 doi:10.1172/JCI41344
- ↑ Tan L, Akahane K, McNally R, Reyskens KM, Ficarro SB, Liu S, Herter-Sprie GS, Koyama S, Pattison MJ, Labella K, Johannessen L, Akbay EA, Wong KK, Frank DA, Marto JA, Look TA, Arthur JS, Eck MJ, Gray NS. Development of Selective Covalent Janus Kinase 3 Inhibitors. J Med Chem. 2015 Aug 27;58(16):6589-606. doi: 10.1021/acs.jmedchem.5b00710. Epub , 2015 Aug 18. PMID:26258521 doi:http://dx.doi.org/10.1021/acs.jmedchem.5b00710
|
