An engineered cysteine at an equivalent position in PDK1 (E166C) has been
addressed by Erlanson et al. using an acrylamide-based “extender” (39, Fig. 14d)
equipped with a (di)sulfide-tag. A subsequent fragment-based disulfide tethering
screen enabled the generation of potent reversible PDK1 inhibitors [94]. Moreover,
the introduction of analogous engineered cysteines has been used in the context of
chemical-genetics approaches to generate probes for kinases such as Aurora kinase
[95] and c-SRC [96].
2.4.2 Inhibitors Targeting the F3 Position
The three c-Jun N-terminal kinases (JNK1–3) are the only kinases known to feature
an accessible cysteine in the F3 position of the αD-helix (αD + 2), eight amino acids
after the gatekeeper residue. This cysteine has been targeted by imatinib-derived
a)
b)
O
N
NH
N
N
N
H
PF-06651600
32
O
N
N
H
N
S
O
O
NH
O
BMX-IN-1
35
N
N
N
H
R
HN
N
33a:
N
N
H
N
N
H
N
H
N
H
O
O
NH
O
O
O
O
CHMFL-BMX-078
36
IC 50 (BMX) = 8 nM
IC 50 (BTK) = 10 nM
IC 50 (BMX) = 11 nM
IC 50 (BTK) = 437 nM
H
N S
O
O
F
R =
R = H
33b:
c)
N
H
N
NH
O
d)
N
N
N
H
N
H
S
S
NH 2
NH
O
N
N
N
N
N
NH 2
N
N
N
O
O
38
37
39
N
N
H
34a (FM-381):
N
N
O
CN
N
O
R = H
R
34b (FM-409): R = Me
MKK7-COV-2
Fig. 14 (a) Examples of irreversible and covalent-reversible JAK3 inhibitors. (b) Irreversible
covalent BMX inhibitors. (c) Irreversible covalent MKK7 inhibitors. (d) Disulfide-tagged covalent
PDK1-E166C inhibitor 39
64
M. Gehringer