Development of Selective Covalent Janus Kinase 3 Inhibitors
Abstract
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 Å 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. As a result, these inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.
- Authors:
-
- Harvard Medical School, Boston, MA (United States); Dana Farber Cancer Inst., Boston, MA (United States)
- Dana Farber Cancer Inst., Boston, MA (United States)
- Univ. of Dundee (United Kingdom)
- Publication Date:
- Research Org.:
- Argonne National Laboratory (ANL), Argonne, IL (United States)
- Sponsoring Org.:
- German Research Foundation (DFG)
- OSTI Identifier:
- 1430281
- Grant/Contract Number:
- HE 6897/1-1
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 58; Journal Issue: 16; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES
Citation Formats
Tan, Li, Akahane, Koshi, McNally, Randall, Reyskens, Kathleen M. S. E., Ficarro, Scott B., Liu, Suhu, Herter-Sprie, Grit S., Koyama, Shohei, Pattison, Michael J., Labella, Katherine, Johannessen, Liv, Akbay, Esra A., Wong, Kwok-Kin, Frank, David A., Marto, Jarrod A., Look, Thomas A., Arthur, J. Simon C., Eck, Michael J., and Gray, Nathanael S. Development of Selective Covalent Janus Kinase 3 Inhibitors. United States: N. p., 2015.
Web. doi:10.1021/acs.jmedchem.5b00710.
Tan, Li, Akahane, Koshi, McNally, Randall, Reyskens, Kathleen M. S. E., Ficarro, Scott B., Liu, Suhu, Herter-Sprie, Grit S., Koyama, Shohei, Pattison, Michael J., Labella, Katherine, Johannessen, Liv, Akbay, Esra A., Wong, Kwok-Kin, Frank, David A., Marto, Jarrod A., Look, Thomas A., Arthur, J. Simon C., Eck, Michael J., & Gray, Nathanael S. Development of Selective Covalent Janus Kinase 3 Inhibitors. United States. https://doi.org/10.1021/acs.jmedchem.5b00710
Tan, Li, Akahane, Koshi, McNally, Randall, Reyskens, Kathleen M. S. E., Ficarro, Scott B., Liu, Suhu, Herter-Sprie, Grit S., Koyama, Shohei, Pattison, Michael J., Labella, Katherine, Johannessen, Liv, Akbay, Esra A., Wong, Kwok-Kin, Frank, David A., Marto, Jarrod A., Look, Thomas A., Arthur, J. Simon C., Eck, Michael J., and Gray, Nathanael S. Mon .
"Development of Selective Covalent Janus Kinase 3 Inhibitors". United States. https://doi.org/10.1021/acs.jmedchem.5b00710. https://www.osti.gov/servlets/purl/1430281.
@article{osti_1430281,
title = {Development of Selective Covalent Janus Kinase 3 Inhibitors},
author = {Tan, Li and Akahane, Koshi and McNally, Randall and Reyskens, Kathleen M. S. E. and Ficarro, Scott B. and Liu, Suhu and Herter-Sprie, Grit S. and Koyama, Shohei and Pattison, Michael J. and Labella, Katherine and Johannessen, Liv and Akbay, Esra A. and Wong, Kwok-Kin and Frank, David A. and Marto, Jarrod A. and Look, Thomas A. and Arthur, J. Simon C. and Eck, Michael J. and Gray, Nathanael S.},
abstractNote = {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 Å 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. As a result, these inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology.},
doi = {10.1021/acs.jmedchem.5b00710},
journal = {Journal of Medicinal Chemistry},
number = 16,
volume = 58,
place = {United States},
year = {Mon Aug 10 00:00:00 EDT 2015},
month = {Mon Aug 10 00:00:00 EDT 2015}
}
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