A second hydrogen bond toward the backbone of Met149 (carbonyl group) was
observed. In this case, the amide NH group serves as a hydrogen bond donor.
A water-mediated hydrogen bond interaction is formed between the NH group of
the urea group (next to the aniline) and the amino group of the Lys93 side chain.
An additional hydrogen bond is established between the NH group of the pyrrolidine
ring and Asn89.
Several dual JNK2/3 inhibitors of the aminopyrazole series have also been
reported in the same publication [37]. In the biochemical assay, SR-11935 shows
a greater than 50-fold isoform selectivity versus JNK1 and potent activity in different
cell-based assays in SHSY5Y cells. At a test concentration of 10 μM, SR-11935
displays a good kinome selectivity. However, in this high-throughput screening
method, a high affinity for JNK1 was observed. SR-11935 penetrates into the
brain (plasma/brain ratio of 2:1) showing both good solubility and good DMPK
properties. Moreover, this inhibitor displays good microsomal stability, when incubated with human or mice liver microsomes as well as no affinity toward CYP450
isoforms 1A2, 2C9, 2D6, and 3A4. In addition, SR-11935 potently inhibits mitochondrial dysfunction and is noncytotoxic.
3 Covalent Inhibitors
The design of covalent kinase inhibitors has resurged [38–40]. In total, a number of
six covalent kinase inhibitors were introduced to the market from 2013 to 2018
(Fig. 12). All these inhibitors possess an α,β-unsaturated amide as electrophilic
moiety, which targets the side chain of a non-catalytic cysteine residue in the
proximity of the ATP-binding site.
As illustrated in the sequence alignment of the JNKs (Fig. 2), all three JNK
isoforms possess a cysteine (Cys114 in JNK1/2 numbering; Cys154 in JNK3
numbering) located in the C-lobe adjacent to the hinge region. In this position, this
cysteine is unique within the kinome and can be targeted by an inhibitor bearing
an electrophilic warhead in a suitable position to form a covalent bond.
3.1 Aminopyrimidine-Based Covalent Inhibitors
The first covalent inhibitors of JNK3 were reported in 2012 by Gray and coworkers
[18]. In search for covalent type II inhibitors of the c-Kit and PDGFR kinases, the
imatinib-derived pan-JNK inhibitor JNK-IN-1 (Fig. 13) was discovered.
A selectivity screening of JNK-IN-1 versus 400 kinases revealed, at a test
concentration of 10 μM, besides binding to the classical imatinib targets (Abl, c-Kit
and DDR1/2), also a strong binding to all three JNK isoforms. Determination of
the biochemical IC 50 values against the latter kinases revealed JNK-IN-1 to be a
moderate inhibitor of all three JNK isoforms.
Inhibitors of c-Jun N-Terminal Kinase 3
215
observed. In this case, the amide NH group serves as a hydrogen bond donor.
A water-mediated hydrogen bond interaction is formed between the NH group of
the urea group (next to the aniline) and the amino group of the Lys93 side chain.
An additional hydrogen bond is established between the NH group of the pyrrolidine
ring and Asn89.
Several dual JNK2/3 inhibitors of the aminopyrazole series have also been
reported in the same publication [37]. In the biochemical assay, SR-11935 shows
a greater than 50-fold isoform selectivity versus JNK1 and potent activity in different
cell-based assays in SHSY5Y cells. At a test concentration of 10 μM, SR-11935
displays a good kinome selectivity. However, in this high-throughput screening
method, a high affinity for JNK1 was observed. SR-11935 penetrates into the
brain (plasma/brain ratio of 2:1) showing both good solubility and good DMPK
properties. Moreover, this inhibitor displays good microsomal stability, when incubated with human or mice liver microsomes as well as no affinity toward CYP450
isoforms 1A2, 2C9, 2D6, and 3A4. In addition, SR-11935 potently inhibits mitochondrial dysfunction and is noncytotoxic.
3 Covalent Inhibitors
The design of covalent kinase inhibitors has resurged [38–40]. In total, a number of
six covalent kinase inhibitors were introduced to the market from 2013 to 2018
(Fig. 12). All these inhibitors possess an α,β-unsaturated amide as electrophilic
moiety, which targets the side chain of a non-catalytic cysteine residue in the
proximity of the ATP-binding site.
As illustrated in the sequence alignment of the JNKs (Fig. 2), all three JNK
isoforms possess a cysteine (Cys114 in JNK1/2 numbering; Cys154 in JNK3
numbering) located in the C-lobe adjacent to the hinge region. In this position, this
cysteine is unique within the kinome and can be targeted by an inhibitor bearing
an electrophilic warhead in a suitable position to form a covalent bond.
3.1 Aminopyrimidine-Based Covalent Inhibitors
The first covalent inhibitors of JNK3 were reported in 2012 by Gray and coworkers
[18]. In search for covalent type II inhibitors of the c-Kit and PDGFR kinases, the
imatinib-derived pan-JNK inhibitor JNK-IN-1 (Fig. 13) was discovered.
A selectivity screening of JNK-IN-1 versus 400 kinases revealed, at a test
concentration of 10 μM, besides binding to the classical imatinib targets (Abl, c-Kit
and DDR1/2), also a strong binding to all three JNK isoforms. Determination of
the biochemical IC 50 values against the latter kinases revealed JNK-IN-1 to be a
moderate inhibitor of all three JNK isoforms.
Inhibitors of c-Jun N-Terminal Kinase 3
215