Recent progress in discovery of novel AAK1 inhibitors: from pain therapy to potential anti-viral agents

Abstract

Adaptor associated kinase 1 (AAK1), a member of the Ark1/Prk1 family of Ser/Thr kinases, is a specific key kinase regulating Thr156 phosphorylation at the μ2 subunit of the adapter complex-2 (AP-2) protein. Due to their important biological functions, AAK1 systems have been validated in clinics for neuropathic pain therapy, and are being explored as potential therapeutic targets for diseases caused by various viruses such as Hepatitis C (HCV), Dengue, Ebola, and COVID-19 viruses and for amyotrophic lateral sclerosis (ALS). Centreing on the advances of drug discovery programs in this field up to 2023, AAK1 inhibitors are discussed from the aspects of the structure-based rational molecular design, pharmacology, toxicology and synthetic routes for the compounds of interest in this review. The aim is to provide the medicinal chemistry community with up-to-date information and to accelerate the drug discovery programs in the field of AAK1 small molecule inhibitors.

Keywords:

• Adaptor associated kinase 1 (AAK1)
• inhibitor
• medicinal chemistry
• therapeutic application

Disclosure statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Funding

This work was supported by the National Natural Science Foundation of China (82073686), Science and Technology Department of Zhejiang Province (2023ZY1014), the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (2023KY210), the Ministry of Science and Technology of China (High-end foreign experts program, G2021017004 and G20200217005), Hangzhou’s “115” plan to introduce overseas intelligence projects (20220597, 20210120 and 20200215), and Hangzhou Normal University startup fund (2019QDL003). C Garrido has the label d’excellence from “la Ligue Nationale contre le Cancer” (France). We thank the Ruban Rose Foundation and the FEDER (EU) for their support.