Protein kinase inhibitors as therapeutics in neurodegenerative and psychiatric disorders: progress, challenges, and recommendations

The role of protein kinase inhibitors as promising future therapeutics in neurodegenerative and psychiatric disorders (NDDs) is currently investigated and actively debated. New compounds and several repurposable molecules licensed for different diseases, including several anticancer drugs, have reached an advanced stage of clinical exploration. In the last decades, no new drugs of relevance have been approved for these devastating disorders, and expectancies from new attempts to approach more effective treatments, including kinase inhibitors, are high. On this basis, we have searched and reviewed 102 clinical trials of interest in NDD listed in official sites, evaluating repositioned or new compounds such as the multispecific inhibitors Bosutinib, Dasatinib, and Nilotinib, the oligospecific inhibitors Masitinib and Saracatinib, and dual/monospecific compounds such as Baricitinib, BIIB094, DNL151, DNL201, DNL747, DNL788, Evobrutinib, Fasudil, Fenebrutinib, IKT148009, Masitinib, Monepantel, MW150, Neflamapimod, Orelabrutinib, Rapamycin, Tideglusib, Tofacitinib, Tolebrutinib, Trametinib, and Vodobatinib. Three additional agents not directly interfering with specific kinases, such as the antisense oligonucleotides Tominersen, Nusinersen, and Tofersen, were included as alternative examples of intervention on pathogenetic processes similarly involved in NDD. Overall, the present state of the art in NDD trials provides preliminary information on the risk/benefit balance of some compounds that are promising, mostly for safety issues, yet do not allow to express a conclusive opinion on their consistent efficacy. However, most important clinical data from a considerable number of Phase 3 studies are yet to come, which may be resolutive to envisage the comprehensive role of this drug class.