covalent inhibitors serendipitously discovered by Gray and co-workers [97]. These
researchers initially aimed to address cysteines located in the catalytic loop of the
PDGFR and c-KIT receptor tyrosine kinases being only accessible in the DFG-out
conformation (subsite I1, see Fig. 4 and Table 1). However, the designed compound
JNK-IN-1 (40, Fig. 16a) showed strong off-target activity on JNKs [15]. Structureguided optimization of this initial hit furnished the potent pan-JNK inhibitor
JNK-IN-8 (41, IC 50 ¼ 4, 19, and 1 nM for JNK1–3, respectively), a compound
Fig. 15 (a) Binding mode of cyanamide-based covalent-reversible JAK3 inhibitor 33b (PDB:
6DB4). The formed isothiourea is involved in several direct and water-mediated hydrogen bonds
contributing to the stabilization of the covalent complex. In the hinge region and the P-loop region,
side chains were omitted for clarity. (b) Binding modes of α-cyanoacrylamide-based covalentreversible JAK3 inhibitor 34b (PDB: 5LWN). The simultaneous presence of both, the covalently
and the non-covalently bound compound (highlighted in cyan and yellow, respectively) is observed
a)
N
N
S
R
b)
F
N
HN
N
H
O
NH
O
42a: R = Me
42b: R = H
O
NH
N
H
N
N
N
HN
O
NMe 2
JNK-IN-8
N
H
N
N
N
JNK-IN-1
HN
O
HN
O
NMe 2
40
41
Fig. 16 (a) Imatinib-derived covalent JNK inhibitors. (b) Pyridinylimidazole-derived covalent
JNK inhibitors
Covalent Kinase Inhibitors: An Overview
65