Type II Kinase Inhibitors

The possibility of controlling cell proliferation and death by inhibition of a specific target kinase offers the opportunity to introduce the concept of targeted therapies in the treatment of cancer, providing a valid alternative to conventional chemotherapy.

In the past, the main effort in kinase inhibitors development was aimed at the identification of highly potent compounds that could mimic ATP binding to the kinase. This led to a first generation of small molecules kinase inhibitors, Type I kinase inhibitors, which target the ATP binding site of the enzyme in its active form. This form is characterized by an open conformation of the activation loop. Most of the approved kinase inhibitors on the market are Type I inhibitors. Because, all Type I inhibitors bind to the ATP site that is common to all kinases, they suffer from widespread cross-reactivity among other members of the kinase target family, leading to poor safety and often to severe side effect profiles in the clinic. Extensive medicinal chemistry optimization efforts are required to modulate the selectivity of Type I drug candidates, and the fierce competition around scaffolds that mimic ATP has led to a very crowded IP space.

New opportunities opened up with the discovery of a second class of kinase inhibitors, Type II kinase inhibitors. This class of compounds binds to the same area occupied by the Type I compounds but also extends to an additional allosteric site, a binding pocket available only in the inactive form of the enzyme. This allosteric site is different from one enzyme to another and offers additional opportunities to control selectivity and introduce IP novelty. As a result, Type II inhibitors have better safety profiles and suffer from fewer side effects. Although only a few of the approved kinase inhibitors are of the Type II class, these capture two-thirds of the market, and include some of the moist successful kinase inhibitors: Imatinib, nilotinib, and sorafenib. Not surprisingly, Type II inhibitors are harder to discover and the development of new kinase inhibitors is still a slow and problematic process.

Dynamix DynamixFit™ platform technology and kinase oriented 'drug discovery engine' are proven to efficiently yield novel, potent Type II kinase inhibitors for a range of kinase targets.

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