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

Xin Xin; Yue Wang; Lele Zhang; Dan Zhang; Leihao Sha; Ziyu Zhu; Xiaoyi Huang; Wuyu Mao; Jifa Zhang

doi:10.1016/j.ejmech.2023.115102

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

Eur J Med Chem. 2023 Feb 15:248:115102. doi: 10.1016/j.ejmech.2023.115102. Epub 2023 Jan 7.

Authors

Xin Xin¹, Yue Wang², Lele Zhang¹, Dan Zhang¹, Leihao Sha¹, Ziyu Zhu¹, Xiaoyi Huang¹, Wuyu Mao³, Jifa Zhang⁴

Affiliations

¹ Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
² Leling Traditional Chinese Medicine Hospital, Leling, 253600, Shandong, China.
³ Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].
⁴ Joint Research Institution of Altitude Health, State Key Laboratory of Biotherapy and Cancer Center, Department of Respiratory and Critical Care Medicine, Institute of Respiratory Health, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China. Electronic address: [email protected].

PMID: 36640459
DOI: 10.1016/j.ejmech.2023.115102

Abstract

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.

Keywords: AAK1; Anti-neuropathic pain; Broad-spectrum antiviral target; Small molecule inhibitors; Structure-activity relationships (SARs).

Publication types

Review

MeSH terms

Alzheimer Disease*
Endocytosis / physiology
Humans
Prospective Studies
Protein Serine-Threonine Kinases*

Substances

Protein Serine-Threonine Kinases