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Papers of the Week

2023 Jan 07

Eur J Med Chem


Development and therapeutic potential of adaptor-associated kinase 1 inhibitors in human multifaceted diseases.


Xin X, Wang Y, Zhang L, Zhang D, Sha L, Zhu Z, Huang X, Mao W, Zhang J
Eur J Med Chem. 2023 Jan 07; 248:115102.
PMID: 36640459.


Adaptor-Associated Kinase 1 (AAK1), a Ser/Thr protein kinase, responsible for regulating clathrin-mediated endocytosis, is ubiquitous in the central nervous system (CNS). AAK1 plays an important role in neuropathic pain and a variety of other human diseases, including viral invasion, Alzheimer's disease, Parkinson's syndrome, etc. Therefore, targeting AAK1 is a promising therapeutic strategy. However, although small molecule AAK1 inhibitors have been vigorously developed, only BMS-986176/LX-9211 has entered clinical trials. Simultaneously, new small molecule inhibitors, including BMS-911172 and LP-935509, exhibited excellent druggability. This review elaborates on the structure, biological function, and disease relevance of AAK1. We emphatically analyze the structure-activity relationships (SARs) of small molecule AAK1 inhibitors based on different binding modalities and discuss prospective strategies to provide insights into novel AAK1 therapeutic agents for clinical practice.