| 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
Janus kinases (JAKs) have a key role in regulating the expression and function of relevant inflammatory cytokines involved in asthma and chronic obstructive pulmonary disease. Herein are described the design, synthesis, and pharmacological evaluation of a series of novel purinone JAK inhibitors with profiles suitable for inhaled administration. Replacement of the imidazopyridine hinge binding motif present in the initial compounds of this series with a pyridone ring resulted in the mitigation of cell cytotoxicity. Further systematic structure-activity relationship (SAR) efforts driven by structural biology studies led to the discovery of pyridone 34, a potent pan-JAK inhibitor with good selectivity, long lung retention time, low oral bioavailability, and proven efficacy in the lipopolysaccharide-induced rat model of airway inflammation by the inhaled route.
Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases.,Bach J, Eastwood P, Gonzalez J, Gomez E, Alonso JA, Fonquerna S, Lozoya E, Orellana A, Maldonado M, Calaf E, Alberti J, Perez J, Andres A, Prats N, Carreno C, Calama E, De Alba J, Calbet M, Miralpeix M, Ramis I J Med Chem. 2019 Oct 14. doi: 10.1021/acs.jmedchem.9b00533. PMID:31609613[12]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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
- ↑ Bach J, Eastwood P, Gonzalez J, Gomez E, Alonso JA, Fonquerna S, Lozoya E, Orellana A, Maldonado M, Calaf E, Alberti J, Perez J, Andres A, Prats N, Carreno C, Calama E, De Alba J, Calbet M, Miralpeix M, Ramis I. Identification of 2-Imidazopyridine and 2-Aminopyridone Purinones as Potent Pan-Janus Kinase (JAK) Inhibitors for the Inhaled Treatment of Respiratory Diseases. J Med Chem. 2019 Oct 14. doi: 10.1021/acs.jmedchem.9b00533. PMID:31609613 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00533
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