Development of Selective Covalent Janus Kinase 3 Inhibitors

Li Tan; Koshi Akahane; Randall McNally; Kathleen M.S.E. Reyskens; Scott B. Ficarro; Suhu Liu; Grit S. Herter-Sprie; Shohei Koyama; Michael J. Pattison; Katherine Labella; Liv Johannessen; Esra A. Akbay; Kwok Kin Wong; David A. Frank; Jarrod A. Marto; Thomas A. Look; J. Simon C. Arthur; Michael J. Eck; Nathanael S. Gray

doi:10.1021/acs.jmedchem.5b00710

Development of Selective Covalent Janus Kinase 3 Inhibitors

Li Tan, Koshi Akahane, Randall McNally, Kathleen M.S.E. Reyskens, Scott B. Ficarro, Suhu Liu, Grit S. Herter-Sprie, Shohei Koyama, Michael J. Pattison, Katherine Labella, Liv Johannessen, Esra A. Akbay, Kwok Kin Wong, David A. Frank, Jarrod A. Marto, Thomas A. Look, J. Simon C. Arthur, Michael J. Eck, Nathanael S. Gray

Research output: Contribution to journal › Article › peer-review

91 Scopus citations

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. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).

Original language	English (US)
Pages (from-to)	6589-6606
Number of pages	18
Journal	Journal of Medicinal Chemistry
Volume	58
Issue number	16
DOIs	https://doi.org/10.1021/acs.jmedchem.5b00710
State	Published - Aug 27 2015

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

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Tan, L., Akahane, K., McNally, R., Reyskens, K. M. S. E., Ficarro, S. B., Liu, S., Herter-Sprie, G. S., Koyama, S., Pattison, M. J., Labella, K., Johannessen, L., Akbay, E. A., Wong, K. K., Frank, D. A., Marto, J. A., Look, T. A., Arthur, J. S. C., Eck, M. J., & Gray, N. S. (2015). Development of Selective Covalent Janus Kinase 3 Inhibitors. Journal of Medicinal Chemistry, 58(16), 6589-6606. https://doi.org/10.1021/acs.jmedchem.5b00710

Tan, L, Akahane, K, McNally, R, Reyskens, KMSE, 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, JSC, Eck, MJ & Gray, NS 2015, 'Development of Selective Covalent Janus Kinase 3 Inhibitors', Journal of Medicinal Chemistry, vol. 58, no. 16, pp. 6589-6606. https://doi.org/10.1021/acs.jmedchem.5b00710

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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 {\AA} 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. (Chemical Equation Presented).",

author = "Li Tan and Koshi Akahane and Randall McNally and Reyskens, {Kathleen M.S.E.} and Ficarro, {Scott B.} and Suhu Liu and Herter-Sprie, {Grit S.} and Shohei Koyama and Pattison, {Michael J.} and Katherine Labella and Liv Johannessen 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.}",

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AU - Akahane, Koshi

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AU - Reyskens, Kathleen M.S.E.

AU - Ficarro, Scott B.

AU - Liu, Suhu

AU - Herter-Sprie, Grit S.

AU - Koyama, Shohei

AU - Pattison, Michael J.

AU - Labella, Katherine

AU - Johannessen, Liv

AU - Akbay, Esra A.

AU - Wong, Kwok Kin

AU - Frank, David A.

AU - Marto, Jarrod A.

AU - Look, Thomas A.

AU - Arthur, J. Simon C.

AU - Eck, Michael J.

AU - Gray, Nathanael S.

PY - 2015/8/27

Y1 - 2015/8/27

N2 - 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. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).

AB - 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. These inhibitors provide a set of useful tools to pharmacologically interrogate JAK3-dependent biology. (Chemical Equation Presented).

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Development of Selective Covalent Janus Kinase 3 Inhibitors

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