pocket involving Cys46 [134]. Recently discovered acrylamide-based covalent
allosteric inhibitors include the AKT inhibitor borussertib (80) [135] and the fragment 81 addressing CDK2 [136]. Moreover, chemical-genetics approaches have
been used to enable covalent targeting of non-canonical binding sites via the
introduction of cysteines. For example, Bührmann et al. recently identified probes
covalently binding to a lipid pocket of p38α MAP kinase cysteine mutants (S251C
and S252C) without labeling the wild-type enzyme [137]. It should, however, be
noted that ligands addressing allosteric- and other non-canonical binding sites are
often identified serendipitously since such pockets tend to be highly plastic and are
frequently not observed in the apo-structures.
2.10 Development of Inhibitors Targeting Lysine or Tyrosine
As mentioned before (see Sect. 2.3), natural products covalently engaging kinases
via lysine residues are well-known. In addition, lysine and tyrosine moieties have
been addressed with synthetic small molecules. For example, activated esters have
been employed to target the catalytic lysine in PI3Kδ by researchers at GSK
[138]. Since the sulfonamide substituent of the reversible PI3Kδ inhibitor
GSK2292767 (82, Fig. 29a) interacts with the ε-amino group of PI3Kδ-Lys779,
replacement of this moiety by activated phenolic esters was considered as a strategy
to address the amino nucleophile. Biochemical potencies of the generated compounds roughly correlated with the leaving group properties of the corresponding
phenolates reaching down to the subnanomolar range for the most activated derivative (83a, IC 50 ¼ 0.6 nM; k inact /K I ¼ 1.9 Â 10
5 M
À1 s
À1 ). Interestingly, analysis of
binding kinetics revealed that k inact was relatively constant in the series while
differences in the overall potency seemed to be mainly driven by K I . This finding
was attributed to a more complex reaction mechanism as compared to the canonical
a)
N
82
GSK2292767
MeO
HN
S O
O
N
H
N
N
O
N
O
N
MeO
N
H
N
N
O
N
N
O
O
R
83b: R = F
83a: R = NO 2
N
N
N
H
N
O
N
H
S R
O O
84b: R = vinyl (NU6300)
84a: R = NH 2 (NU6102)
84c: R = Et (NU6310)
b)
Fig. 29 Examples of lysine-targeted covalent kinase inhibitors. (a) Design of activated esters
addressing the catalytic lysine in PI3Kδ. (b) Vinyl sulfones targeting the solvent-exposed Lys89
in CDK2
Covalent Kinase Inhibitors: An Overview
79
allosteric inhibitors include the AKT inhibitor borussertib (80) [135] and the fragment 81 addressing CDK2 [136]. Moreover, chemical-genetics approaches have
been used to enable covalent targeting of non-canonical binding sites via the
introduction of cysteines. For example, Bührmann et al. recently identified probes
covalently binding to a lipid pocket of p38α MAP kinase cysteine mutants (S251C
and S252C) without labeling the wild-type enzyme [137]. It should, however, be
noted that ligands addressing allosteric- and other non-canonical binding sites are
often identified serendipitously since such pockets tend to be highly plastic and are
frequently not observed in the apo-structures.
2.10 Development of Inhibitors Targeting Lysine or Tyrosine
As mentioned before (see Sect. 2.3), natural products covalently engaging kinases
via lysine residues are well-known. In addition, lysine and tyrosine moieties have
been addressed with synthetic small molecules. For example, activated esters have
been employed to target the catalytic lysine in PI3Kδ by researchers at GSK
[138]. Since the sulfonamide substituent of the reversible PI3Kδ inhibitor
GSK2292767 (82, Fig. 29a) interacts with the ε-amino group of PI3Kδ-Lys779,
replacement of this moiety by activated phenolic esters was considered as a strategy
to address the amino nucleophile. Biochemical potencies of the generated compounds roughly correlated with the leaving group properties of the corresponding
phenolates reaching down to the subnanomolar range for the most activated derivative (83a, IC 50 ¼ 0.6 nM; k inact /K I ¼ 1.9 Â 10
5 M
À1 s
À1 ). Interestingly, analysis of
binding kinetics revealed that k inact was relatively constant in the series while
differences in the overall potency seemed to be mainly driven by K I . This finding
was attributed to a more complex reaction mechanism as compared to the canonical
a)
N
82
GSK2292767
MeO
HN
S O
O
N
H
N
N
O
N
O
N
MeO
N
H
N
N
O
N
N
O
O
R
83b: R = F
83a: R = NO 2
N
N
N
H
N
O
N
H
S R
O O
84b: R = vinyl (NU6300)
84a: R = NH 2 (NU6102)
84c: R = Et (NU6310)
b)
Fig. 29 Examples of lysine-targeted covalent kinase inhibitors. (a) Design of activated esters
addressing the catalytic lysine in PI3Kδ. (b) Vinyl sulfones targeting the solvent-exposed Lys89
in CDK2
Covalent Kinase Inhibitors: An Overview
79