Probing Allosteric Kinase Modulators as Next Game-Changers in Fighting Neurodegeneration.

Kinases represent one of the main targets of interest in recent years, completely revolutionizing small molecule anticancer therapy. Particularly, several medicinal chemistry strategies (e.g., covalent and allosteric inhibitors) allowed overcoming of the challenging selectivity issue, thus enabling the massive clinical translation of kinase inhibitors. However, the same success has not been detected yet for tackling neurodegenerative diseases, despite plenty of experimental evidence regarding kinases' pivotal roles in onset and development of neurodegenerative processes. In this perspective we highlight the therapeutic potential of allosteric kinase modulators in this respect, by showcasing the developmental processes and neuroprotective properties of CNS-directed allosteric kinases modulators developed so far. Moreover, we present additional kinases whose modulation is related to neuroprotection and featured by validated allosteric modulators not yet exploited in this context. This, along with a critical discussion on main drawbacks and future directions, may foster the development of allosteric kinase modulators in neurodegenerative diseases.