| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Experimental Therapeutics, Preclinical Pharmacology |
Parker Hughes Cancer Center [R. K. N., F. M. U.], Departments of Structural Biology [E. A. S., S. G., C. M.], Experimental Oncology [R. K. N., F. M. U.], Biochemistry [S. M.], and Chemistry [X-P. L.], and Drug Discovery Program [E. A. S., X-P. L., S. G., C. M., F. M. U.], Hughes Institute, St. Paul, Minnesota 55113
A novel homology model of the kinase domain of Janus kinase (JAK) 3 was used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 Å x 11 Å x 20 Å, with a volume of 
530 Å3 available for inhibitor binding. Modeling studies indicated that 4-(phenyl)-amino-6,7-dimethoxyquinazoline (parent compound WHI-258) would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967, a key residue in the catalytic site of JAK3. These predictions were consistent with docking studies indicating that compounds containing a 4'-OH group, WHI-P131 [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P154 [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P97 [4-(3',5'-dibromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], were likely to bind favorably to JAK3, with estimated Kis ranging from 0.6 to 2.3 µM. These compounds inhibited JAK3 in immune complex kinase assays in a dose-dependent fashion. In contrast, compounds lacking the 4'-OH group, WHI-P79 [4-(3'-bromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P111 [4-(3'-bromo-4'-methylphenyl)-amino-6,7-dimethoxyquinazoline], WHI-P112 [4-(2',5'-dibromophenyl)-amino-6,7-dimethoxyquinazoline], WHI-P132 [4-(2'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline], and WHI-P258 [4-(phenyl)-amino-6,7-dimethoxyquinazoline], were predicted to bind less strongly, with estimated Kis ranging from 28 to 72 µM. These compounds did not show any significant JAK3 inhibition in kinase assays. Furthermore, the lead dimethoxyquinazoline compound, WHI-P131, which showed potent JAK3-inhibitory activity (IC50 of 78 µM), did not inhibit JAK1 and JAK2, the ZAP/SYK family tyrosine kinase SYK, the TEC family tyrosine kinase BTK, the SRC family tyrosine kinase LYN, or the receptor family tyrosine kinase insulin receptor kinase, even at concentrations as high as 350 µM. WHI-P131 induced apoptosis in JAK3-expressing human leukemia cell lines NALM-6 and LC1;19 but not in melanoma (M24-MET) or squamous carcinoma (SQ20B) cells. Leukemia cells were not killed by dimethoxyquinazoline compounds that were inactive against JAK3. WHI-P131 inhibited the clonogenic growth of JAK3-positive leukemia cell lines DAUDI, RAMOS, LC1;19, NALM-6, MOLT-3, and HL-60 (but not JAK3-negative BT-20 breast cancer, M24-MET melanoma, or SQ20B squamous carcinoma cell lines) in a concentration-dependent fashion. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia, the most common form of childhood cancer.
This article has been cited by other articles:
|
|
 |
|
  P. Bonvini, E. Zorzi, L. Mussolin, G. Monaco, M. Pigazzi, G. Basso, and A. Rosolen The effect of the cyclin-dependent kinase inhibitor flavopiridol on anaplastic large cell lymphoma cells and relationship with NPM-ALK kinase expression and activity Haematologica, July 1, 2009; 94(7): 944 - 955. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. W. Tyner, D. K. Walters, S. G. Willis, M. Luttropp, J. Oost, M. Loriaux, H. Erickson, A. S. Corbin, T. O'Hare, M. C. Heinrich, et al. RNAi screening of the tyrosine kinome identifies therapeutic targets in acute myeloid leukemia Blood, February 15, 2008; 111(4): 2238 - 2245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Cortes, M. Perez-G, M. D. Rivas, and J. Zamorano Kaempferol Inhibits IL-4-Induced STAT6 Activation by Specifically Targeting JAK3 J. Immunol., September 15, 2007; 179(6): 3881 - 3887. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Acacia de Sa Pinheiro, A. Morrot, S. Chakravarty, M. Overstreet, J. H. Bream, P. M. Irusta, and F. Zavala IL-4 induces a wide-spectrum intracellular signaling cascade in CD8+ T cells J. Leukoc. Biol., April 1, 2007; 81(4): 1102 - 1110. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Lucet, E. Fantino, M. Styles, R. Bamert, O. Patel, S. E. Broughton, M. Walter, C. J. Burns, H. Treutlein, A. F. Wilks, et al. The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinase inhibitor Blood, January 1, 2006; 107(1): 176 - 183. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.-J. M. van de Geijn, J. Gits, L. H. J. Aarts, C. Heijmans-Antonissen, and I. P. Touw G-CSF receptor truncations found in SCN/AML relieve SOCS3-controlled inhibition of STAT5 but leave suppression of STAT3 intact Blood, August 1, 2004; 104(3): 667 - 674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Mangan, S. G. Rane, A. D. Kang, A. Amanullah, B. C. Wong, and E. P. Reddy Mechanisms associated with IL-6-induced up-regulation of Jak3 and its role in monocytic differentiation Blood, June 1, 2004; 103(11): 4093 - 4101. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H.-J. Kim, J. Hart, N. Knatz, M. W. Hall, and M. D. Wewers Janus Kinase 3 Down-Regulates Lipopolysaccharide-Induced IL-1{beta}-Converting Enzyme Activation by Autocrine IL-10 J. Immunol., April 15, 2004; 172(8): 4948 - 4955. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T. Barata, V. A. Boussiotis, J. A. Yunes, A. A. Ferrando, L. A. Moreau, J. P. Veiga, S. E. Sallan, A. T. Look, L. M. Nadler, and A. A. Cardoso IL-7-dependent human leukemia T-cell line as a valuable tool for drug discovery in T-ALL Blood, March 1, 2004; 103(5): 1891 - 1900. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Lindemann, M. Benczik, and S. L. Gaffen Anti-apoptotic Signaling by the Interleukin-2 Receptor Reveals a Function for Cytoplasmic Tyrosine Residues within the Common gamma (gamma c) Receptor Subunit J. Biol. Chem., March 14, 2003; 278(12): 10239 - 10249. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Huang, Y. Wang, S. B. Cogut, B. S. Mitchell, and L. M. Graves Inhibition of Nucleoside Transport by Protein Kinase Inhibitors J. Pharmacol. Exp. Ther., February 1, 2003; 304(2): 753 - 760. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Uckun, B. A. Roers, B. Waurzyniak, X.-P. Liu, and M. Cetkovic-Cvrlje Janus kinase 3 inhibitor WHI-P131/JANEX-1 prevents graft-versus-host disease but spares the graft-versus-leukemia function of the bone marrow allografts in a murine bone marrow transplantation model Blood, May 13, 2002; 99(11): 4192 - 4199. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. M. Uckun, J. Thoen, H. Chen, E. Sudbeck, C. Mao, R. Malaviya, X.-P. Liu, and C.-L. Chen CYP1A-Mediated Metabolism of the Janus Kinase-3 Inhibitor 4-(4'-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline: Structural Basis for Inactivation by Regioselective O-Demethylation Drug Metab. Dispos., January 1, 2002; 30(1): 74 - 85. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cetkovic-Cvrlje, B. A. Roers, B. Waurzyniak, X.-P. Liu, and F. M. Uckun Targeting Janus kinase 3 to attenuate the severity of acute graft-versus-host disease across the major histocompatibility barrier in mice Blood, September 1, 2001; 98(5): 1607 - 1613. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Lindauer, T. Loerting, K. R. Liedl, and R. T. Kroemer Prediction of the structure of human Janus kinase 2 (JAK2) comprising the two carboxy-terminal domains reveals a mechanism for autoregulation Protein Eng. Des. Sel., January 1, 2001; 14(1): 27 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Malaviya, C.-L. Chen, C. Navara, R. Malaviya, X.-P. Liu, M. Keenan, B. Waurzyniak, and F. M. Uckun Treatment of Allergic Asthma by Targeting Janus Kinase 3-Dependent Leukotriene Synthesis in Mast Cells with 4-(3',5'-Dibromo-4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline (WHI-P97) J. Pharmacol. Exp. Ther., December 1, 2000; 295(3): 912 - 926. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. J O'Shea, R. Visconti, T. P Cheng, and M. Gadina Jaks and Stats as therapeutic targets Ann Rheum Dis, November 1, 2000; 59(90001): i115 - 118. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Ghosh, Y. Zheng, X. Jun, S. Mahajan, C. Mao, E. A. Sudbeck, and F. M. Uckun Specificity of {{alpha}}-Cyano-{{beta}}-Hydroxy-{{beta}}-Methyl-N-[4-(Trifluoromethoxy)Phenyl]-Propenamide as an Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase Clin. Cancer Res., December 1, 1999; 5(12): 4264 - 4272. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. M. Uckun, O. Ek, X.-P. Liu, and C.-L. Chen In Vivo Toxicity and Pharmacokinetic Features of the Janus Kinase 3 Inhibitor WHI-P131 [4-(4'Hydroxyphenyl)-Amino-6,7-Dimethoxyquinazoline] Clin. Cancer Res., October 1, 1999; 5(10): 2954 - 2962. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Malaviya, D. Zhu, I. Dibirdik, and F. M. Uckun Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis J. Biol. Chem., September 17, 1999; 274(38): 27028 - 27038. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. E. Tibbles, A. Vassilev, H. Wendorf, D. Schonhoff, D. Zhu, D. Lorenz, B. Waurzyniak, X.-P. Liu, and F. M. Uckun Role of a JAK3-dependent Biochemical Signaling Pathway in Platelet Activation and Aggregation J. Biol. Chem., May 18, 2001; 276(21): 17815 - 17822. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Mahajan, A. Vassilev, N. Sun, Z. Ozer, C. Mao, and F. M. Uckun Transcription Factor STAT5A Is a Substrate of Bruton's Tyrosine Kinase in B Cells J. Biol. Chem., August 10, 2001; 276(33): 31216 - 31228. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
