NUAK激酶：信号传导机制与治疗应用

NUAK kinases: Signaling mechanisms and therapeutic applications.

作者信息

Cullen Nicole M, Rosston Peter, Tufail Bakhtawar, D'Armond Anne E, Patel Ayushi, Khosravi Dara H, Collins-Burow Bridgette M, Hoang Van T, Martin Elizabeth C, Drewry David H, Burow Matthew E, Alahari Suresh K

机构信息

Department of Medicine, Section of Hematology and Oncology, Tulane University School of Medicine, New Orleans, Louisiana, USA.

Structural Genomics Consortium, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA; Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

出版信息

J Biol Chem. 2025 Aug 5;301(9):110565. doi: 10.1016/j.jbc.2025.110565.

DOI:10.1016/j.jbc.2025.110565

PMID:40774384

Abstract

The novel (nua) kinases 1 and 2 are two of 12 AMP-activated protein-related kinases whose signaling pathways are involved in cancer progression, as well as neurologic, fibrotic, and inflammatory diseases. Currently, there are 80 Food and Drug Administration-approved kinase inhibitors which target roughly 24 of the 500+ known human kinases, leaving most kinases underexplored, including NUAK1 and NUAK2. Thus, there is a critical need for selective inhibition of NUAK1 and NUAK2 signaling. Here, we review the protein structure, known upstream regulators and downstream targets, and expression profiles of NUAK1 and NUAK2 in cancerous compared to noncancerous tissue. We also delineate the biological roles and signaling pathways of the NUAK kinases in a range of malignancies, focusing on cancer but also covering noncancerous physiology, and the therapeutic potential of NUAK kinase inhibition. We summarize the known small-molecule NUAK kinase inhibitors in preclinical models and one inhibitor in clinical trials. This review highlights the signaling mechanisms and therapeutic value of targeting NUAK kinase signaling pathways with specific, small-molecule NUAK inhibitors.

摘要

新型（nua）激酶1和2是12种与AMP激活蛋白相关的激酶中的两种，其信号通路涉及癌症进展以及神经、纤维化和炎症性疾病。目前，有80种经美国食品药品监督管理局批准的激酶抑制剂，它们靶向500多种已知人类激酶中的约24种，使得包括NUAK1和NUAK2在内的大多数激酶未得到充分研究。因此，迫切需要选择性抑制NUAK1和NUAK2信号传导。在此，我们综述了NUAK1和NUAK2的蛋白质结构、已知的上游调节因子和下游靶点，以及与非癌组织相比，它们在癌组织中的表达谱。我们还阐述了NUAK激酶在一系列恶性肿瘤中的生物学作用和信号通路，重点是癌症，但也涵盖非癌生理学，以及抑制NUAK激酶的治疗潜力。我们总结了临床前模型中已知的小分子NUAK激酶抑制剂以及一种正在进行临床试验的抑制剂。本综述强调了用特异性小分子NUAK抑制剂靶向NUAK激酶信号通路的信号传导机制和治疗价值。