[155]. The inhibitor 3,4-dichloro-2-ethoxy-N-(2,2,6,6-tetramethylpiperidin-4-yl)
benzenesulfonamide targets the inactive form of IKKβ by binding between the
kinase domain and ubiquitin-like domain abrogating activation of IKK as suggested
by molecular dynamic simulations. The compound potently inhibited IκBβ/α
phosphorylation and NF-κB activation in cells and opens the opportunity for the
design of novel type-IV inhibitors for this key signalling kinase.
Even though the field of allosteric inhibitor development is in its infancy for
most kinase targets, it has now been established that type-III and type-IV inhibitors
offer several unique advantages when compared to conventional ATP competitive
compounds. In particular, allosteric inhibitors are often exclusively selective for
kinase isoforms or even mutants by exploring target specific mechanism of
activation. They abrogate therefore not simply catalytic activity but also modulate
scaffolding function of the kinase and its interaction with regulatory domains
or proteins. Type-III and type-IV inhibitors open therefore opportunities for the
development of inhibitors with new mode of action utilizing new and unexplored
chemical scaffolds. However, despite these advantages, the design of novel lead
structures remains a challenging task as no general strategies have been developed
for their identification and optimization. Hence, allosteric inhibitors are often
found serendipitously in high-throughput screens and by structural studies [13].
We predict, however, that type-III and type-IV inhibitors will play a major role
in the future in kinase drug discovery.
5 Conclusions and Outlook
With 48 kinase targeting drugs that are currently approved, protein kinases have
developed into one of the most promising areas of drug discovery. Recent approvals
increasingly target kinases that play a role in a number of diverse diseases with small
patient populations, such as rare oncogenic rearrangements and mutants which have
been validated as dominant drivers of tumour development and growth. The current
clinical inhibitors utilize predominantly conventional ATP mimetic scaffolds for
the development of canonical type-I, type-I½ and type-II inhibitors. However, also
new type of inhibitors such as covalent inhibitors [11] and allosteric inhibitors [13]
have now entered clinical development pipelines and have been approved for
clinical use.
Allosteric inhibitors are particularly attractive for the development of inhibitors
with exclusive selectivity for closely related isoforms and in some cases even
for oncogenic mutants. These recent developments may open other therapeutic
areas for kinase inhibitor development that have not been successfully targeted
by kinase inhibitors because of selectivity issues or the rigid hydrophobic nature
of conventional ATP mimetic scaffolds that make it difficult to develop kinase
inhibitors, for instance, for neurological applications or long-term systemic use.
In addition, allosteric inhibitors also modulate scaffolding function of kinases
and how they interact with regulatory proteins. These properties could be used
Function, Structure and Topology of Protein Kinases
17
benzenesulfonamide targets the inactive form of IKKβ by binding between the
kinase domain and ubiquitin-like domain abrogating activation of IKK as suggested
by molecular dynamic simulations. The compound potently inhibited IκBβ/α
phosphorylation and NF-κB activation in cells and opens the opportunity for the
design of novel type-IV inhibitors for this key signalling kinase.
Even though the field of allosteric inhibitor development is in its infancy for
most kinase targets, it has now been established that type-III and type-IV inhibitors
offer several unique advantages when compared to conventional ATP competitive
compounds. In particular, allosteric inhibitors are often exclusively selective for
kinase isoforms or even mutants by exploring target specific mechanism of
activation. They abrogate therefore not simply catalytic activity but also modulate
scaffolding function of the kinase and its interaction with regulatory domains
or proteins. Type-III and type-IV inhibitors open therefore opportunities for the
development of inhibitors with new mode of action utilizing new and unexplored
chemical scaffolds. However, despite these advantages, the design of novel lead
structures remains a challenging task as no general strategies have been developed
for their identification and optimization. Hence, allosteric inhibitors are often
found serendipitously in high-throughput screens and by structural studies [13].
We predict, however, that type-III and type-IV inhibitors will play a major role
in the future in kinase drug discovery.
5 Conclusions and Outlook
With 48 kinase targeting drugs that are currently approved, protein kinases have
developed into one of the most promising areas of drug discovery. Recent approvals
increasingly target kinases that play a role in a number of diverse diseases with small
patient populations, such as rare oncogenic rearrangements and mutants which have
been validated as dominant drivers of tumour development and growth. The current
clinical inhibitors utilize predominantly conventional ATP mimetic scaffolds for
the development of canonical type-I, type-I½ and type-II inhibitors. However, also
new type of inhibitors such as covalent inhibitors [11] and allosteric inhibitors [13]
have now entered clinical development pipelines and have been approved for
clinical use.
Allosteric inhibitors are particularly attractive for the development of inhibitors
with exclusive selectivity for closely related isoforms and in some cases even
for oncogenic mutants. These recent developments may open other therapeutic
areas for kinase inhibitor development that have not been successfully targeted
by kinase inhibitors because of selectivity issues or the rigid hydrophobic nature
of conventional ATP mimetic scaffolds that make it difficult to develop kinase
inhibitors, for instance, for neurological applications or long-term systemic use.
In addition, allosteric inhibitors also modulate scaffolding function of kinases
and how they interact with regulatory proteins. These properties could be used
Function, Structure and Topology of Protein Kinases
17