demonstrated that type-II inhibitors have slow off-rates resulting in prolonged
target residence times. However, comparing larger data sets, slow off-rates have
also been reported for canonical type-I inhibitors suggesting that a diversity of
structural mechanisms contribute to target residency [22, 99, 100].
The type-II pharmacophore shares a common heterocyclic hinge-binding
head group which is connected with typically an amide, urea or another hydrophilic
linker with a hydrophobic deep pocket binding moiety. Besides the important
hinge-binding donor and acceptor interactions, contacts with the highly conserved
aspartate backbone from the DFG motif and glutamate present in the αC-helix are
common [13, 101].
4.1 Noncanonical Binding Modes
The dynamic nature of the kinase catalytic domain gives rise to many noncanonical
binding modes that target additional pockets or that constitute intermediate
states between classical type-I and type-II binding modes discussed above. One
variant is the type-I½ binding mode, an ATP competitive binding mode recognizing
an either active or an intermediate conformation of the DFG motif which is not
fully in the canonical out conformation. Often also an αC-out conformation is
observed in type-I½ structures resulting in distorted or interrupted R-spines [102].
An interesting type-I½ inhibitor is, for instance, a derivative of the p38 type-I
inhibitor skepinone-L, which interacts with the hinge region inducing the Gly110
backbone flip while inserting into the R-Spine with a thiophene moiety (Fig. 6a)
[103]. Similar to some type-II inhibitors, the induced structural changes result
in prolonged target residency and slow off-rate kinetics.
Flexible structure elements such as the αC-helix, P-loop or the A-loop can adopt
several types of inactive conformations in addition to the DFG-in and DFG-out state.
Besides canonical type-I, type-II and type-I½ binding, different ways of trapping
inactive, high-energy conformations of a given kinase, creating less solvent exposed
and more buried cavities, can be found in diverse studies. Lapatinib targets a DFG-in
conformation inducing large, inactivating conformational rearrangements unique
to the kinase domain in epidermal growth factor receptor (EGF1R) explaining
the exceptional selectivity of this drug [104]. The DFG-in inhibitor GSK2606414
targets a unique binding pocket created by an inactive activation segment
conformation in the protein kinase R (PKR)-like endoplasmic reticulum kinase
(PERK) again resulting in exclusive selectivity [105, 106].
P-loop folded conformations have been found for a set of kinases which
harbour aromatic amino acids such as Tyr and Phe at the tip of this loop region
[107]. In the active state, these aromatic residues orient their side chains away
from the ATP site supporting interaction with the ATP cofactor. In contrast, crystal
structures of inhibitor complexes showed that these aromatic side chains can
interact with the inhibitor resulting in distortion of the P-loop conformation and
capture the P-loop inside the ATP-binding active site. Inhibitors inducing these
12
S. Röhm et al.
target residence times. However, comparing larger data sets, slow off-rates have
also been reported for canonical type-I inhibitors suggesting that a diversity of
structural mechanisms contribute to target residency [22, 99, 100].
The type-II pharmacophore shares a common heterocyclic hinge-binding
head group which is connected with typically an amide, urea or another hydrophilic
linker with a hydrophobic deep pocket binding moiety. Besides the important
hinge-binding donor and acceptor interactions, contacts with the highly conserved
aspartate backbone from the DFG motif and glutamate present in the αC-helix are
common [13, 101].
4.1 Noncanonical Binding Modes
The dynamic nature of the kinase catalytic domain gives rise to many noncanonical
binding modes that target additional pockets or that constitute intermediate
states between classical type-I and type-II binding modes discussed above. One
variant is the type-I½ binding mode, an ATP competitive binding mode recognizing
an either active or an intermediate conformation of the DFG motif which is not
fully in the canonical out conformation. Often also an αC-out conformation is
observed in type-I½ structures resulting in distorted or interrupted R-spines [102].
An interesting type-I½ inhibitor is, for instance, a derivative of the p38 type-I
inhibitor skepinone-L, which interacts with the hinge region inducing the Gly110
backbone flip while inserting into the R-Spine with a thiophene moiety (Fig. 6a)
[103]. Similar to some type-II inhibitors, the induced structural changes result
in prolonged target residency and slow off-rate kinetics.
Flexible structure elements such as the αC-helix, P-loop or the A-loop can adopt
several types of inactive conformations in addition to the DFG-in and DFG-out state.
Besides canonical type-I, type-II and type-I½ binding, different ways of trapping
inactive, high-energy conformations of a given kinase, creating less solvent exposed
and more buried cavities, can be found in diverse studies. Lapatinib targets a DFG-in
conformation inducing large, inactivating conformational rearrangements unique
to the kinase domain in epidermal growth factor receptor (EGF1R) explaining
the exceptional selectivity of this drug [104]. The DFG-in inhibitor GSK2606414
targets a unique binding pocket created by an inactive activation segment
conformation in the protein kinase R (PKR)-like endoplasmic reticulum kinase
(PERK) again resulting in exclusive selectivity [105, 106].
P-loop folded conformations have been found for a set of kinases which
harbour aromatic amino acids such as Tyr and Phe at the tip of this loop region
[107]. In the active state, these aromatic residues orient their side chains away
from the ATP site supporting interaction with the ATP cofactor. In contrast, crystal
structures of inhibitor complexes showed that these aromatic side chains can
interact with the inhibitor resulting in distortion of the P-loop conformation and
capture the P-loop inside the ATP-binding active site. Inhibitors inducing these
12
S. Röhm et al.