Virtual screening to successfully identify novel janus kinase 3 inhibitors: a sequential focused screening approach.

In an effort to identify novel Janus kinase 3 inhibitors, a sequential focused screening approach was adopted to search our in-house chemical database. By biologically testing only 79 selected compounds, we successfully identified 19 compounds showing IC 50 < 20 microM, with four of them in the nanomolar range. Particularly, a 3,5-disubstituted pyrazolo[4,3- d]pyrimidine scaffold emerged as a promising candidate for further lead optimization. With the advantages of efficiency and flexibility, this approach may be utilized to identify leads for other therapeutic targets.

[1]  A. Sher,et al.  A Critical Role for IL-21 in Regulating Immunoglobulin Production , 2002, Science.

[2]  X. P. Liu,et al.  In vivo toxicity and pharmacokinetic features of the janus kinase 3 inhibitor WHI-P131 [4-(4'hydroxyphenyl)-amino-6,7- dimethoxyquinazoline. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[3]  S. Emanuel,et al.  Synthesis and discovery of pyrazine-pyridine biheteroaryl as a novel series of potent vascular endothelial growth factor receptor-2 inhibitors. , 2005, Journal of medicinal chemistry.

[4]  M. Strnad,et al.  Pyrazolo[4,3-d]pyrimidines as new generation of cyclin-dependent kinase inhibitors. , 2003, Bioorganic & medicinal chemistry letters.

[5]  Xin Chen,et al.  Simplified staurosporine analogs as potent JAK3 inhibitors. , 2007, Bioorganic & medicinal chemistry letters.

[6]  S Stanley Young,et al.  Initial compound selection for sequential screening. , 2002, Current opinion in drug discovery & development.

[7]  David W. Anderson,et al.  SP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[8]  S. Rane,et al.  Janus kinases: components of multiple signaling pathways , 2000, Oncogene.

[9]  Jürgen Bajorath,et al.  Integration of virtual and high-throughput screening , 2002, Nature Reviews Drug Discovery.

[10]  J. Johnston,et al.  Regulation of JAK3 expression and activation in human B cells and B cell malignancies. , 1995, Journal of immunology.

[11]  W. Patrick Walters,et al.  A guide to drug discovery: Designing screens: how to make your hits a hit , 2003, Nature Reviews Drug Discovery.

[12]  F. Uckun,et al.  Targeting Janus Kinase 3 in Mast Cells Prevents Immediate Hypersensitivity Reactions and Anaphylaxis* , 1999, The Journal of Biological Chemistry.

[13]  James E. Thompson.  JAK protein kinase inhibitors. , 2005, Drug news & perspectives.

[14]  M. Säemann,et al.  Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor , 2004, European Surgery.

[15]  James E. Thompson and.  Photochemical Preparation of a Pyridone Containing Tetracycle: A Jak Protein Kinase Inhibitor. , 2010 .

[16]  H Wang,et al.  High Throughput Screening: Early Successes Indicate a Promising Future , 2001, Journal of biomolecular screening.

[17]  W. Farrar,et al.  Tyrphostin AG-490 Regulation of as Novel Molecular Targets for the JAK3, STAT, and MAPK Signaling Pathways , 1999 .

[18]  Kevin P Cross,et al.  Comparison of methods for sequential screening of large compound sets. , 2006, Combinatorial chemistry & high throughput screening.

[19]  D. S. James,et al.  Naphthyl ketones: a new class of Janus kinase 3 inhibitors. , 2000, Bioorganic & medicinal chemistry letters.

[20]  M. Stahl,et al.  Scaffold hopping. , 2004, Drug discovery today. Technologies.

[21]  M. Sliwkowski,et al.  Structure of the Epidermal Growth Factor Receptor Kinase Domain Alone and in Complex with a 4-Anilinoquinazoline Inhibitor* , 2002, The Journal of Biological Chemistry.

[22]  L. Wodicka,et al.  A small molecule–kinase interaction map for clinical kinase inhibitors , 2005, Nature Biotechnology.

[23]  Eric D. Brown,et al.  High throughput screening identifies novel inhibitors of Escherichia coli dihydrofolate reductase that are competitive with dihydrofolate. , 2003, Bioorganic & medicinal chemistry letters.

[24]  P. Cohen,et al.  The specificities of protein kinase inhibitors: an update. , 2003, The Biochemical journal.

[25]  E. Garvey,et al.  Small molecule modulators of HIV Rev/Rev response element interaction identified by random screening. , 2002, Antiviral research.

[26]  P. Furet,et al.  Use of a pharmacophore model for the design of EGF-R tyrosine kinase inhibitors: 4-(phenylamino)pyrazolo[3,4-d]pyrimidines. , 1997, Journal of medicinal chemistry.

[27]  M F Engels,et al.  Smart screening: approaches to efficient HTS. , 2001, Current opinion in drug discovery & development.

[28]  D K Jones-Hertzog,et al.  Use of recursive partitioning in the sequential screening of G-protein-coupled receptors. , 1999, Journal of pharmacological and toxicological methods.

[29]  B. Kahan,et al.  Janus kinase 3: a novel target for selective transplant immunosupression , 2004, Expert opinion on therapeutic targets.