Top Med Chem (2021) 36: 203–224
https://doi.org/10.1007/7355_2020_98
© Springer Nature Switzerland AG 2020
Published online: 2 April 2020
Inhibitors of c-Jun N-Terminal Kinase 3
Pierre Koch
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2 Reversible Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.1 Prototypical JNK Inhibitor SP600125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.2 Aminopyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.3 2-Alkylsulfanyl-5-(pyridin-4-yl)imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
2.4 Aminopyrazole Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
3 Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.1 Aminopyrimidine-Based Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.2 Pyridinylimidazole-Based Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Abstract The serine/threonine kinase c-Jun N-terminal kinase (JNK) 3 is
implicated in the pathogenesis of various disorders ranging from neurodegenerative
diseases to inflammation, metabolic disease, diabetes, liver diseases, and cancer.
Although the number of publications reporting on JNK3 inhibitors has been
decreasing in the last few years, this enzyme still constitutes an attractive target.
Within the last years, significant progress in the design of JNK3 inhibitors displaying
good to excellent selectivity versus other protein kinases has been achieved.
However, the development of a JNK-isoform-selective JNK3 inhibitor, which may
serve as a tool compound in animal studies to further evaluate the role of JNK3
as a therapeutic target, is highly desirable. This chapter summarizes the progress
in the development of reversible and irreversible inhibitors of JNK3.
Keywords c-Jun N-terminal kinase 3, Covalent inhibitors, JNK3, MAP kinase
family, Reversible inhibitors, Selectivity
P. Koch (*)
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls Universität Tübingen, Tübingen, Germany
e-mail: pierre.koch@uni-tuebingen.de
https://doi.org/10.1007/7355_2020_98
© Springer Nature Switzerland AG 2020
Published online: 2 April 2020
Inhibitors of c-Jun N-Terminal Kinase 3
Pierre Koch
Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 204
2 Reversible Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.1 Prototypical JNK Inhibitor SP600125 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.2 Aminopyrimidines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
2.3 2-Alkylsulfanyl-5-(pyridin-4-yl)imidazoles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
2.4 Aminopyrazole Derivatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 213
3 Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.1 Aminopyrimidine-Based Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215
3.2 Pyridinylimidazole-Based Covalent Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218
4 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 221
Abstract The serine/threonine kinase c-Jun N-terminal kinase (JNK) 3 is
implicated in the pathogenesis of various disorders ranging from neurodegenerative
diseases to inflammation, metabolic disease, diabetes, liver diseases, and cancer.
Although the number of publications reporting on JNK3 inhibitors has been
decreasing in the last few years, this enzyme still constitutes an attractive target.
Within the last years, significant progress in the design of JNK3 inhibitors displaying
good to excellent selectivity versus other protein kinases has been achieved.
However, the development of a JNK-isoform-selective JNK3 inhibitor, which may
serve as a tool compound in animal studies to further evaluate the role of JNK3
as a therapeutic target, is highly desirable. This chapter summarizes the progress
in the development of reversible and irreversible inhibitors of JNK3.
Keywords c-Jun N-terminal kinase 3, Covalent inhibitors, JNK3, MAP kinase
family, Reversible inhibitors, Selectivity
P. Koch (*)
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls Universität Tübingen, Tübingen, Germany
e-mail: pierre.koch@uni-tuebingen.de