The Outcomes of Small-Molecule Kinase Inhibitors and the Role of ROCK2 as a Molecular Target for the Treatment of Alzheimer's Disease

Background: Alzheimer's disease is rapidly becoming a major threat to public health, with an increasing number of individuals affected as the world's population ages. In this sense, stud-ies have been carried out aiming at the identification of new small-molecule kinase inhibitors useful for the treatment of Alzheimer's disease. Objective: In the present study, we investigated the compounds developed as inhibitors of different protein kinases associated with the pathogenesis of Alzheimer's disease. Methods: The applied methodology was the use of the Clarivate Analytics Integrity and ClinicalTri-als.com databases. Moreover, we highlight ROCK2 as a promising target despite being little studied for this purpose. A careful structure-activity relationship analysis of the ROCK2 inhibitors was per -formed to identify important structural features and fragments for the interaction with the kinase ac-tive site, aiming to rationally design novel potent and selective inhibitors. Results: We were able to notice some structural characteristics that could serve as the basis to better guide the rational design of new ROCK2 inhibitors as well as some more in-depth characteristics regarding the topology of the active site of both isoforms of these enzymes, thereby identifying dif-ferences that could lead to planning more selective compounds. Conclusion: We hope that this work can be useful to update researchers working in this area, ena-bling the emergence of new ideas and a greater direction of efforts for designing new ROCK2 inhib-itors to identify new therapeutic alternatives for Alzheimer's disease.