they can bind simultaneous with ATP to an active DFG-in conformation of a
kinase disrupting catalytic function by distorting the kinase fold. Some type-III
inhibitors also bind in an ATP competitive manner and stabilize the inactive
DFG-out state as demonstrated by allosteric inhibitors targeting p38, FAK or
IGF1R kinases [110–112]. The N-phenylsulfonamide LIMK2 inhibitor published
by Goodwin et al. is the first example addressing tyrosin-like kinases (TKL) in
an allosteric way. The high potency and the exceptional selectivity of the compound
have been achieved by an DFG-out/αC-out binding mode which has been confirmed
by a co-crystal structure [113].
The most prominent examples of allosteric type-III inhibitors are clinically
approved MEK1/2 inhibitors trametinib, cobimetinib, binimetinib [114–116]
and many similar drug candidates that are currently in the clinical development
pipeline. Trametinib shows exceptionally high efficiency, potency and selectivity,
and it was the first allosteric kinase inhibitor approved by the FDA for the
treatment of adult B-RafV600E and V600K-mutated metastatic melanoma [117].
The compound binds to the allosteric back-pocket adjacent to the ATP-binding
site making hydrogen bounds to the conserved β3-lysine and hydrophobic contacts
to the β5-strand, the activation loop and the αC-helix. Upon binding the αC-helix
gets displaced leading to inhibition of the kinase activity. The activation loop further
adopts a closed conformation prohibiting substrate binding [118, 119]. Stimulated
by the success of the first-generation MEK inhibitors, many diverse allosteric
MEK1/2 inhibitors occupying this pocket have been reported and are now tested
clinically in diverse cancer indications such as non-small cell lung cancer (NSCLC),
leukaemia and thyroid and colon cancer [120]. About 30 MEK kinase structures in
complex with small-molecule allosteric inhibitors and ATP have been cocrystallized providing inside in important structural aspects of inhibitor binding.
Figure 7a exemplifies the allosteric pocket of refametinib in complex with
ATP [121].
A potent and isoform selective type-III inhibitor has been published recently by
Bagal et al. targeting tropomyosin receptor kinases (TrkA) [122]. As confirmed
by structural studies, the inhibitor interacts with an allosteric pocket adjacent to
the ATP-binding site accessible in the DFG-out conformation of this kinase.
Hydrophobic interactions and hydrogen bonds stabilize the inhibitor also taking
advantage of the structurally diverse TrkA juxtamembrane domain. As the targeted
pocket in the juxtamembrane domain is unique to TrKA, the compound gains
selectivity over the closely related TrK family members TrKB and TrKC
[123, 124]. The compound has demonstrated to be efficient in preclinical pain
models [122].
Type-IV inhibitors bind reversibly to induced binding pocket that are in
contrast to type-III inhibitors distantly located from the ATP-binding site. The ability
of type-IV inhibitors inducing structural changes in the catalytic domain results
often in inhibition, but not all induced or stable pockets targeted in kinases
also abrogate catalytic activity [125]. For instance, a unique binding mode has
been observed for GNF-2 with binds to the myristate pocket located at the
C-terminal lobe of ABL (Fig. 7b) [126]. GNF-2 and its derivative have an interesting
14
S. Röhm et al.
kinase disrupting catalytic function by distorting the kinase fold. Some type-III
inhibitors also bind in an ATP competitive manner and stabilize the inactive
DFG-out state as demonstrated by allosteric inhibitors targeting p38, FAK or
IGF1R kinases [110–112]. The N-phenylsulfonamide LIMK2 inhibitor published
by Goodwin et al. is the first example addressing tyrosin-like kinases (TKL) in
an allosteric way. The high potency and the exceptional selectivity of the compound
have been achieved by an DFG-out/αC-out binding mode which has been confirmed
by a co-crystal structure [113].
The most prominent examples of allosteric type-III inhibitors are clinically
approved MEK1/2 inhibitors trametinib, cobimetinib, binimetinib [114–116]
and many similar drug candidates that are currently in the clinical development
pipeline. Trametinib shows exceptionally high efficiency, potency and selectivity,
and it was the first allosteric kinase inhibitor approved by the FDA for the
treatment of adult B-RafV600E and V600K-mutated metastatic melanoma [117].
The compound binds to the allosteric back-pocket adjacent to the ATP-binding
site making hydrogen bounds to the conserved β3-lysine and hydrophobic contacts
to the β5-strand, the activation loop and the αC-helix. Upon binding the αC-helix
gets displaced leading to inhibition of the kinase activity. The activation loop further
adopts a closed conformation prohibiting substrate binding [118, 119]. Stimulated
by the success of the first-generation MEK inhibitors, many diverse allosteric
MEK1/2 inhibitors occupying this pocket have been reported and are now tested
clinically in diverse cancer indications such as non-small cell lung cancer (NSCLC),
leukaemia and thyroid and colon cancer [120]. About 30 MEK kinase structures in
complex with small-molecule allosteric inhibitors and ATP have been cocrystallized providing inside in important structural aspects of inhibitor binding.
Figure 7a exemplifies the allosteric pocket of refametinib in complex with
ATP [121].
A potent and isoform selective type-III inhibitor has been published recently by
Bagal et al. targeting tropomyosin receptor kinases (TrkA) [122]. As confirmed
by structural studies, the inhibitor interacts with an allosteric pocket adjacent to
the ATP-binding site accessible in the DFG-out conformation of this kinase.
Hydrophobic interactions and hydrogen bonds stabilize the inhibitor also taking
advantage of the structurally diverse TrkA juxtamembrane domain. As the targeted
pocket in the juxtamembrane domain is unique to TrKA, the compound gains
selectivity over the closely related TrK family members TrKB and TrKC
[123, 124]. The compound has demonstrated to be efficient in preclinical pain
models [122].
Type-IV inhibitors bind reversibly to induced binding pocket that are in
contrast to type-III inhibitors distantly located from the ATP-binding site. The ability
of type-IV inhibitors inducing structural changes in the catalytic domain results
often in inhibition, but not all induced or stable pockets targeted in kinases
also abrogate catalytic activity [125]. For instance, a unique binding mode has
been observed for GNF-2 with binds to the myristate pocket located at the
C-terminal lobe of ABL (Fig. 7b) [126]. GNF-2 and its derivative have an interesting
14
S. Röhm et al.