NUAK family kinase 1 (NUAK1) (NUAK1)

NUAK family kinase 1 (NUAK1), also known as ARK5, is a serine/threonine-protein kinase belonging to the AMP-activated protein kinase (AMPK) family [1]. It plays a pivotal role in cellular adaptation to metabolic stress, such as nutrient deprivation and hypoxia, by maintaining energy homeostasis and preventing apoptosis [1, 4]. NUAK1 is activated by the tumor suppressor LKB1 and is frequently overexpressed in various malignancies, including colorectal, pancreatic, and breast cancers [2, 5]. In these contexts, it is associated with poor prognosis, increased metastatic potential, and resistance to chemotherapy [5]. It is particularly critical in MYC-driven cancers, where it supports the high metabolic demands and protein synthesis requirements of rapidly proliferating cells [4]. By regulating the actin cytoskeleton through phosphorylation of substrates like MYPT1, NUAK1 also facilitates tumor cell migration and invasion [2, 3]. Inhibition of NUAK1 has been shown to sensitize cancer cells to metabolic stress and reduce their invasive capabilities in preclinical models [2, 3]. Small-molecule inhibitors like HTH-01-015 and WZ4003 are currently used as research tools to study its therapeutic potential [2, 3]. However, clinical translation requires addressing challenges related to kinase selectivity among the AMPK-related family and potential impacts on normal metabolic regulation [2, 6].

Other names

ARK5AMP-activated protein kinase-related kinase 5KIAA0537SNF1/AMP kinase-related kinase

ATP-competitive inhibition of the NUAK1 kinase domain to block phosphorylation of downstream targets like MYPT1 and AKT, thereby inhibiting cell survival and motility [2, 3].