longer be activated [135, 136]. The phosphoinositide-dependent protein kinase-1
(PDK1) inhibitors RS1 and RS2 target a hydrophobic motif called PDK1-interacting
fragment (PIF) pocket, exclusively found at the N-terminal lobe of PDK1 [137].
Interaction of these inhibitors allosterically inactivates the catalytic function
of PDK1.
AKT1 kinase is another interesting target for the design of allosteric
inhibitors by offering an alternative mode of inhibition, as all previous described
ATP-competitive inhibitors failed in clinical trials so far [132]. The complex
domain architecture of AKT provides the possibility to target the kinase
allosterically, as demonstrated by the highly selective AKT1 antagonist
MK-2206 [138–140]. The compound binds via hydrogen bond and π-π stacking
interactions at the interface between the AKT kinase domain and the pleckstrin
homology (PH) domain locking the kinase in an inactive conformation preventing
membrane association. In this closed so-called PH-in state, the ATP-binding
pocket is no longer accessible. In addition, activation of AKT1 is prevented by
abrogating recruitment to the plasma membrane. Other described allosteric AKT
inhibitors address, for instance, the PH domain preventing structural rearrangements
for activation [141–144].
The activation of cyclin-dependent kinases (CDKs) is reliant on their regulatory
proteins of the cyclin family, and CDKs are key regulators of cell cycle control
[145, 146]. CDKs have been extensively studied as drug targets, and their role in
cancer and inflammatory diseases and three CDK4/6 inhibitors has been approved
for treatment of cancer [147]. For CDK2 it has been shown that the kinase activity
can be interrupted by targeting an allosteric pocket formed between the αC-helix
and the β3-, β4- and β5-strand of the N-lobe [148]. The simultaneous binding of
two 8-anilino-1-naphthalene sulfonate (ANS) inhibitors changes the orientation
of the β-strands, moving the αC-helix outwards and prohibit the binding of
the cyclins [149, 150]. However, these inhibitors are at a very early stage
of development and have still not been optimized for in vivo use.
As we outlined above, epithermal growth factor receptor (EGFR) kinases
are activated by asymmetric dimerization where the C-terminal lobe of the
activator kinase activates the receiver kinase domain. EGFR can form either
homo- or heterodimeric structures that are reminiscent on the interactions
observed in cyclin-dependent activation of CDKs [53, 151]. The recently published
inhibitor EAI045 binds to an allosteric pocked formed by displacement of the
αC-helix interfering with this activating interaction of the EGFR kinase domain.
The excellent selectivity of this allosteric inhibitor allows mutant-selective
targeting of EGFR, sparing EGFR wild-type. In combination with the therapeutic
antibody cetuximab, EAI045 potently inhibits the mutants EGFR(L858R/T790M)
and EGFR(L858R/T790M/C797S) efficiently overcoming resistance of these
mutants to current ATP competitive inhibitors [152]. Further allosteric EGFR
inhibitors are in development and open new opportunities for the treatment
of diverse cancer types such as non-small cell lung cancer (NSCLC) [153, 154].
The first potent and selective I kappa-B kinase β (IKKß) allosteric
inhibitor which prevents IKKß activation has been publish by Liu et al. in 2018
16
S. Röhm et al.
(PDK1) inhibitors RS1 and RS2 target a hydrophobic motif called PDK1-interacting
fragment (PIF) pocket, exclusively found at the N-terminal lobe of PDK1 [137].
Interaction of these inhibitors allosterically inactivates the catalytic function
of PDK1.
AKT1 kinase is another interesting target for the design of allosteric
inhibitors by offering an alternative mode of inhibition, as all previous described
ATP-competitive inhibitors failed in clinical trials so far [132]. The complex
domain architecture of AKT provides the possibility to target the kinase
allosterically, as demonstrated by the highly selective AKT1 antagonist
MK-2206 [138–140]. The compound binds via hydrogen bond and π-π stacking
interactions at the interface between the AKT kinase domain and the pleckstrin
homology (PH) domain locking the kinase in an inactive conformation preventing
membrane association. In this closed so-called PH-in state, the ATP-binding
pocket is no longer accessible. In addition, activation of AKT1 is prevented by
abrogating recruitment to the plasma membrane. Other described allosteric AKT
inhibitors address, for instance, the PH domain preventing structural rearrangements
for activation [141–144].
The activation of cyclin-dependent kinases (CDKs) is reliant on their regulatory
proteins of the cyclin family, and CDKs are key regulators of cell cycle control
[145, 146]. CDKs have been extensively studied as drug targets, and their role in
cancer and inflammatory diseases and three CDK4/6 inhibitors has been approved
for treatment of cancer [147]. For CDK2 it has been shown that the kinase activity
can be interrupted by targeting an allosteric pocket formed between the αC-helix
and the β3-, β4- and β5-strand of the N-lobe [148]. The simultaneous binding of
two 8-anilino-1-naphthalene sulfonate (ANS) inhibitors changes the orientation
of the β-strands, moving the αC-helix outwards and prohibit the binding of
the cyclins [149, 150]. However, these inhibitors are at a very early stage
of development and have still not been optimized for in vivo use.
As we outlined above, epithermal growth factor receptor (EGFR) kinases
are activated by asymmetric dimerization where the C-terminal lobe of the
activator kinase activates the receiver kinase domain. EGFR can form either
homo- or heterodimeric structures that are reminiscent on the interactions
observed in cyclin-dependent activation of CDKs [53, 151]. The recently published
inhibitor EAI045 binds to an allosteric pocked formed by displacement of the
αC-helix interfering with this activating interaction of the EGFR kinase domain.
The excellent selectivity of this allosteric inhibitor allows mutant-selective
targeting of EGFR, sparing EGFR wild-type. In combination with the therapeutic
antibody cetuximab, EAI045 potently inhibits the mutants EGFR(L858R/T790M)
and EGFR(L858R/T790M/C797S) efficiently overcoming resistance of these
mutants to current ATP competitive inhibitors [152]. Further allosteric EGFR
inhibitors are in development and open new opportunities for the treatment
of diverse cancer types such as non-small cell lung cancer (NSCLC) [153, 154].
The first potent and selective I kappa-B kinase β (IKKß) allosteric
inhibitor which prevents IKKß activation has been publish by Liu et al. in 2018
16
S. Röhm et al.