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.

P1/2, N=72, Recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd. | Not yet recruiting --> Recruiting

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.

P1/2, N=72, Not yet recruiting, Hangzhou Hanx Biopharmaceuticals, Ltd.

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.

Clinicopathological analysis confirms that upregulated NUAK1 expression correlates with poor prognosis and chemotherapy resistance in human GC. Our findings demonstrate that the signaling axis NUAK1/STAT5/GLI1 promotes cancer cell expansion and tumorigenesis and indicate that NUAK1 is an attractive therapeutic target and prognostic factor in GC.

P1, N=20, Completed, Hangzhou Hanx Biopharmaceuticals, Ltd. | Active, not recruiting --> Completed

Significant leukemia load reductions in bone marrow, where disease originated, were also achieved in both responders (AM7577/AM8096), implicating that HX301 might be a potentially more effective therapy than those only affecting peripheral leukemic cells. Altogether, narazaciclib can potentially be a candidate treatment for a subset of AML with CSF1Rhi and/or mutant FLT3-ITD variants, particularly second generation FLT3 inhibitor resistant variants.

This study first revealed the relationship between ARK5 and mitochondrial morphological dynamics. Thus, our outcomes show novel aspects of mitochondrial biology of ARK5, which can afford a more advanced treatment approach for unfavorable MM expressing ARK5.

Our results showed that NUAK1 kinase controls mTOR subcellular localization and induces Akt phosphorylation, demonstrating that NUAK1 regulates the growth factor-dependent activation of Akt signaling. Therefore, targeting NUAK1, or co-targeting it with Akt or mTOR inhibitors, may be effective in cancers with hyperactivated Akt signaling.

P1, N=36, Recruiting, Onconova Therapeutics, Inc. | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024