NUAK family kinase 1 (NUAK1)

NUAK family kinase 1 (NUAK1), commonly referred to as AMPK-related protein kinase 5 (ARK5), is a serine/threonine kinase belonging to the AMPK family that is activated by the upstream kinase LKB1 [UniProt, NCBI Gene]. It serves as a key mediator of cell survival and metabolic adaptation, allowing cells to withstand environmental stressors such as hypoxia and glucose starvation [UniProt, PubMed: 22819534]. In many malignancies, NUAK1 is upregulated and facilitates tumor progression by promoting epithelial-mesenchymal transition (EMT), cell invasion, and resistance to chemotherapy-induced apoptosis [PubMed: 22819534]. Notably, NUAK1 has been identified as a synthetic lethal target in MYC-driven cancers, where its inhibition leads to catastrophic metabolic stress and cell death [PubMed: 22819534]. Beyond oncology, it plays roles in regulating protein synthesis through the phosphorylation of MYPT1 and influences cellular senescence [UniProt, PubMed: 24561921]. Therapeutic strategies targeting NUAK1 involve the development of selective small-molecule inhibitors like HTH-01-015 and WZ4003, which are designed to block its ATP-binding pocket [PubMed: 24561921, PubMed: 23548900]. These inhibitors have demonstrated efficacy in preclinical models by impairing the adaptive capacity of cancer cells to survive in harsh microenvironments [PubMed: 24561921, PubMed: 22819534]. Consequently, NUAK1 represents a promising target for precision medicine, particularly in tumors exhibiting high MYC activity or metabolic flexibility [PubMed: 22819534].

Other names

AMPK-related protein kinase 5ARK5KIAA0537NUAK family kinase 1

Small molecule inhibition of the kinase catalytic activity by competing with ATP binding, thereby preventing phosphorylation of downstream substrates like MYPT1 [PubMed: 24561921, PubMed: 23548900].