NUAK1 (NUAK Family Kinase 1)

NUAK1 is upregulated in DKD, promoting senescence via reactive oxygen species-tumor protein 53 under transcriptional activation by E26 transformation-specific 1, while Asiatic acid (AA) directly binds NUAK1 to suppress these pathological processes. NUAK1 emerges as a therapeutic target for DKD, and AA provides a natural scaffold for NUAK1 inhibitor development, offering a strategy to combat diabetes-related renal decline.

Proliferation-related genes (PKM2, Notch1), invasion-related genes (Gab2, NUAK1), the apoptosis-related gene Bcl-2, and the proliferation marker Ki67 are positively correlated with specific ultrasonographic features in young patients with advanced breast cancer, suggesting a link between imaging phenotypes and molecular markers of aggressiveness.

Notably, both chloroquine treatment and ULK1-S757E transfection abolished the OSI-027/WZ4003 synergy. Moreover, elevated ARK5 expression was observed in HCC specimens and was independently associated with an unfavorable recurrence-free survival (RFS). Our findings propose a novel strategy for augmenting sensitivity to OSI-027 in HCC, further underscoring the significance of ARK5 and autophagy as cancer therapeutic targets.

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.

Moreover, TAZ promoted human leukocyte antigen G (HLA-G) surface expression and increased NUAK1 kinase in EVTs thereby maintaining its own expression. In summary, the transcriptional coactivator TAZ plays a multifaceted role in the development of the EVT cell lineage by controlling different biological processes that initiate and preserve differentiation.

Mechanistically, NUAK1/2 enhances mTOR activity by suppressing the activity of p53, thereby promoting NSCLC cell growth and metastasis through the promotion of aerobic glycolysis and PPP. Our findings suggest that NUAK1/2 plays a crucial role in glucose reprogramming and tumorigenesis in NSCLC cells, indicating that targeting NUAK1/2 may represent a potential therapeutic strategy for NSCLC metabolism.

This study revealed a novel role for NUAK1, which promotes the transcriptional expression of PD-L1 by activating GSK3β/β-catenin signaling pathway, leading to immune escape of hepatocellular carcinoma. Registry and the registration no. of the study/trial: Not applicable.

Targeting the mevalonate pathway with CRISPR knockout or the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) inhibitor simvastatin amplifies NUAK1 inhibition-mediated ICD and antitumor activity, while cholesterol dampens ROS and ICD, and therefore also dampens tumor suppression. The combination of NUAK1 inhibitor and statin enhances the efficacy of anti-PD-1 therapy. Collectively, our study unveils the promise of blocking the mevalonate-cholesterol pathway in conjunction with ICD-targeted immunotherapy.

The expression levels of NUAK1 are significantly increased in STAD, and this heightened expression correlates with diminished OS, DSS, and PFI among affected patients. These observations indicate that NUAK1 has the potential to function as a prognostic biomarker for STAD and may represent a viable therapeutic target for intervention in its management.

We report here the discovery of Nuak1 inhibitors originating from HTS hit 9 with excellent selectivity and the subsequent medicinal chemistry optimization program, supported by structural information from the first crystal structures of a Nuak1 chimeric protein which provided insights into the binding modes of our compounds. These efforts yielded a nanomolar cell potent, highly selective and brain penetrant Nuak1 inhibitor UCB9386 (56) suitable for in vivo pharmacological studies for central nervous system (CNS) disorders.

Importantly, pretreating breast cancer cells with mTOR inhibitors blocked the metabolic reprogramming and tumor-promoting effect of NUAK1/2. Therefore, targeting NUAKs may represent a novel therapeutic strategy for the treatment of breast cancer.

Furthermore, virtual drug screening identified T21195 as an inhibitor of NADK-S64 phosphorylation, and T21195 synergized with osimertinib to reverse acquired resistance by inducing ROS accumulation. Collectively, these findings highlight the role of the NUAK1-NADK axis in governing osimertinib resistance in NSCLC and indicate the potential of targeting this axis as a strategy for circumventing resistance.