4 Conclusion
Numerous very potent reversible and irreversible small molecule JNK3 inhibitors
displaying IC 50 values down to the subnanomolar range have been reported within
the last years. The binding modes for most of these inhibitors were determined
by X-ray experiments. Several examples of recently published JNK3 inhibitors are
showing very good to excellent selectivity within the kinome. Most of the discussed
inhibitors display no or only low affinity versus non-JNK members of the MAP
kinase family.
Moreover, some JNK3 inhibitors displaying intra-JNK selectivity have been
reported. Within the class of aminopyrazole-derived reversible inhibitors, several
examples of JNK2/3 inhibitors, e.g., SR-11935, showing selectivity versus JNK1
have been reported. Among them, aminopyrazole 10 represents the first reported
potent JNK3 inhibitor showing very good JNK-isoform selectivity. However, its
kinome-wide selectivity has not been reported.
The targeting of the thiol group present in the non-conserved Cys154, which is
located adjacent to the ATP-binding site in JNK3, by electrophilic warheads
resulted in the very potent irreversible pan-JNK inhibitors LN2332 and JNK-IN-8.
Both compounds show an excellent selectivity within the human kinome. The
latter covalent inhibitor, which is also active in cellular assays, is the only available
high-quality kinase probe for JNK1/2/3 so far and might be used to further
investigate the role of the JNKs in various disorders.
Acknowledgments Many thanks to Dr. Francesco Ansideri and Stanislav Andreev for helpful
discussions. Dr. Ansideri is also acknowledged for providing Fig. 1. Kristina Schmidt is gratefully
acknowledged for proofreading of the manuscript.
Compliance with Ethical Standards
Conflict of Interest: Author declares that he has no conflict of interest.
Ethical approval: This article does not contain any studies with human participants performed by
the author.
References
1. Barr RK, Bogoyevitch MA (2001) The c-Jun N-terminal protein kinase family of mitogenactivated protein kinases (JNK MAPKs). Int J Biochem Cell B 33:1047–1063. https://doi.org/
10.1016/S1357-2725(01)00093-0
2. Bogoyevitch MA (2006) The isoform-specific functions of the c-Jun N-terminal kinases
(JNKs): differences revealed by gene targeting. BioEssays 28:923–934. https://doi.org/10.
1002/bies.20458
3. Bogoyevitch MA, Kobe B (2006) Uses for JNK: the many and varied substrates of the c-Jun
N-terminal kinases. Microbiol Mol Biol Rev 70:1061. https://doi.org/10.1128/MMBR.
00025-06
Inhibitors of c-Jun N-Terminal Kinase 3
221
Numerous very potent reversible and irreversible small molecule JNK3 inhibitors
displaying IC 50 values down to the subnanomolar range have been reported within
the last years. The binding modes for most of these inhibitors were determined
by X-ray experiments. Several examples of recently published JNK3 inhibitors are
showing very good to excellent selectivity within the kinome. Most of the discussed
inhibitors display no or only low affinity versus non-JNK members of the MAP
kinase family.
Moreover, some JNK3 inhibitors displaying intra-JNK selectivity have been
reported. Within the class of aminopyrazole-derived reversible inhibitors, several
examples of JNK2/3 inhibitors, e.g., SR-11935, showing selectivity versus JNK1
have been reported. Among them, aminopyrazole 10 represents the first reported
potent JNK3 inhibitor showing very good JNK-isoform selectivity. However, its
kinome-wide selectivity has not been reported.
The targeting of the thiol group present in the non-conserved Cys154, which is
located adjacent to the ATP-binding site in JNK3, by electrophilic warheads
resulted in the very potent irreversible pan-JNK inhibitors LN2332 and JNK-IN-8.
Both compounds show an excellent selectivity within the human kinome. The
latter covalent inhibitor, which is also active in cellular assays, is the only available
high-quality kinase probe for JNK1/2/3 so far and might be used to further
investigate the role of the JNKs in various disorders.
Acknowledgments Many thanks to Dr. Francesco Ansideri and Stanislav Andreev for helpful
discussions. Dr. Ansideri is also acknowledged for providing Fig. 1. Kristina Schmidt is gratefully
acknowledged for proofreading of the manuscript.
Compliance with Ethical Standards
Conflict of Interest: Author declares that he has no conflict of interest.
Ethical approval: This article does not contain any studies with human participants performed by
the author.
References
1. Barr RK, Bogoyevitch MA (2001) The c-Jun N-terminal protein kinase family of mitogenactivated protein kinases (JNK MAPKs). Int J Biochem Cell B 33:1047–1063. https://doi.org/
10.1016/S1357-2725(01)00093-0
2. Bogoyevitch MA (2006) The isoform-specific functions of the c-Jun N-terminal kinases
(JNKs): differences revealed by gene targeting. BioEssays 28:923–934. https://doi.org/10.
1002/bies.20458
3. Bogoyevitch MA, Kobe B (2006) Uses for JNK: the many and varied substrates of the c-Jun
N-terminal kinases. Microbiol Mol Biol Rev 70:1061. https://doi.org/10.1128/MMBR.
00025-06
Inhibitors of c-Jun N-Terminal Kinase 3
221