Top Med Chem (2021) 36: 225–256
https://doi.org/10.1007/7355_2020_96
© Springer Nature Switzerland AG 2020
Published online: 19 March 2020
Covalent Janus Kinase 3 Inhibitors
Matthias Gehringer and Michael Forster
Contents
1 JAK3 and the Janus Kinase Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2 Covalent JAK3 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Abstract During the past decade, covalent targeting has experienced a revival,
especially in the kinase field. Addressing non-conserved cysteine residues by
targeted covalent inhibitors has enabled the design of ligands with high selectivity
in the kinome and has led to five currently approved drugs (1–5; early September
2018). Covalent inhibition was also the prime strategy for the selective targeting
of JAK3, a member of the Janus kinase (JAK) family of non-receptor tyrosine
kinases. JAKs are key regulators of the immune system. However, while the
function of JAK3 is mainly limited to immune signaling, the remaining three
JAK family members also fulfill other essential functions outside the
immune system. Therefore, JAK3 has long been discussed as a promising target
for the treatment of inflammatory and autoimmune disorders with limited side
effects. Until recently, however, the development of sufficiently JAK3-selective
small molecules was impeded by the high similarity of the JAKs’ ATP binding
pockets. Addressing Cys909, which is a serine in the other JAK family members,
with electrophilic warheads, has recently enabled the generation of JAK3 inhibitors
with unprecedented selectivity in the JAK family and the kinome. These compounds
have now paved the way for the in-depth examination of JAK3-dependent signaling
in cells and in vivo. Current research efforts culminated in the development of
PF-06651600, a phase II clinical candidate from Pfizer under investigation for the
treatment of rheumatoid arthritis, inflammatory bowel disease, and alopecia areata.
M. Gehringer (*) and M. Forster
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls University Tuebingen, Tuebingen, Germany
e-mail: Matthias.gehringer@uni-tuebingen.de; Michael.forster@uni-tuebingen.de
https://doi.org/10.1007/7355_2020_96
© Springer Nature Switzerland AG 2020
Published online: 19 March 2020
Covalent Janus Kinase 3 Inhibitors
Matthias Gehringer and Michael Forster
Contents
1 JAK3 and the Janus Kinase Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226
2 Covalent JAK3 Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3 Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252
Abstract During the past decade, covalent targeting has experienced a revival,
especially in the kinase field. Addressing non-conserved cysteine residues by
targeted covalent inhibitors has enabled the design of ligands with high selectivity
in the kinome and has led to five currently approved drugs (1–5; early September
2018). Covalent inhibition was also the prime strategy for the selective targeting
of JAK3, a member of the Janus kinase (JAK) family of non-receptor tyrosine
kinases. JAKs are key regulators of the immune system. However, while the
function of JAK3 is mainly limited to immune signaling, the remaining three
JAK family members also fulfill other essential functions outside the
immune system. Therefore, JAK3 has long been discussed as a promising target
for the treatment of inflammatory and autoimmune disorders with limited side
effects. Until recently, however, the development of sufficiently JAK3-selective
small molecules was impeded by the high similarity of the JAKs’ ATP binding
pockets. Addressing Cys909, which is a serine in the other JAK family members,
with electrophilic warheads, has recently enabled the generation of JAK3 inhibitors
with unprecedented selectivity in the JAK family and the kinome. These compounds
have now paved the way for the in-depth examination of JAK3-dependent signaling
in cells and in vivo. Current research efforts culminated in the development of
PF-06651600, a phase II clinical candidate from Pfizer under investigation for the
treatment of rheumatoid arthritis, inflammatory bowel disease, and alopecia areata.
M. Gehringer (*) and M. Forster
Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences,
Eberhard Karls University Tuebingen, Tuebingen, Germany
e-mail: Matthias.gehringer@uni-tuebingen.de; Michael.forster@uni-tuebingen.de