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NUAK2 Inhibitors, KHKI-01128 and KHKI-01215, Exhibit Potent Anticancer Activity Against SW480 Colorectal Cancer Cells
Seung Hyeong Lee1, Su Ah Kim1,2, Su Jin Park1,2
1Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology, Daejeon, Republic of Korea.
Background/Aim:
NUAK family kinase 2 (NUAK2) is a promising target for cancer therapeutics due to its reported role in protein phosphorylation, a critical process in cancer cell survival, proliferation, invasion, and senescence. This study aimed to identify novel inhibitors that disrupt NUAK2 activity. We have already identified two KRICT Hippo kinase inhibitor (KHKI) compounds, such as KHKI-01128 and KHKI-01215. Our aim was to evaluate the impact of KHKI-01128 and KHKI-01215 on NUAK2 activity and elucidate its mechanism in colorectal cancer cells.
Materials And Methods:
To evaluate anticancer properties of these inhibitors, four in vitro assays in the SW480 cell line (time-resolved fluorescence resonance energy transfer assay, KINOMEscan kinase profiling, viability, and apoptosis assays) and two pharmacological mechanism analyses (Gene Set Enrichment Analysis and western blotting) were performed.
Results:
KHKI-01128 and KHKI-01215 exhibited potent inhibitory activity against NUAK2 (half-maximal inhibitory concentration=0.024±0.015 μM and 0.052±0.011 μM, respectively). These inhibitors suppressed cell proliferation, with half-maximal inhibitory concentrations of 1.26±0.17 μM and 3.16±0.30 μM, respectively, and induced apoptosis of SW480 cells. Gene Set Enrichment Analysis revealed negative enrichment scores of -0.84 for KHKI-01128 (false-discovery rate=0.70) and 1.37 for KHKI-01215 (false-discovery rate=0.18), indicating that both effectively suppressed the expression of YES1-associated transcriptional regulator (YAP) target genes.
Conclusion:
These results suggest that KHKI-01128 and KHKI-01215 are potent NUAK2 inhibitors with promising potential for pharmaceutical applications.
Insights
Two novel compounds, KRICT Hippo kinase inhibitor (KHKI)-01128 and KHKI-01215, effectively inhibit NUAK2 activity. These NUAK2 inhibitors show potent anticancer properties by suppressing proliferation and inducing apoptosis in colorectal cancer cells.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Research
- Pharmacology
Background:
- NUAK family kinase 2 (NUAK2) plays a critical role in cancer cell survival, proliferation, and invasion through protein phosphorylation.
- NUAK2 is identified as a promising therapeutic target for developing novel cancer treatments.
- KRICT Hippo kinase inhibitor (KHKI) compounds, specifically KHKI-01128 and KHKI-01215, have been identified as potential NUAK2 inhibitors.
Purpose of the Study:
- To evaluate the inhibitory effects of KHKI-01128 and KHKI-01215 on NUAK2 activity.
- To elucidate the mechanism of action of these compounds in colorectal cancer cells.
- To assess the potential of these compounds as pharmaceutical agents for cancer therapy.
Main Methods:
- In vitro assays including time-resolved fluorescence resonance energy transfer, KINOMEscan kinase profiling, viability, and apoptosis assays were performed on SW480 cells.
- Pharmacological mechanism analysis involved Gene Set Enrichment Analysis and western blotting.
- The study evaluated the half-maximal inhibitory concentration (IC50) for both kinase inhibition and antiproliferative effects.
Main Results:
- KHKI-01128 and KHKI-01215 demonstrated potent NUAK2 inhibition with low micromolar IC50 values.
- Both compounds significantly suppressed colorectal cancer cell proliferation and induced apoptosis in SW480 cells.
- Gene Set Enrichment Analysis indicated that these inhibitors effectively suppressed the expression of YAP target genes, suggesting a mechanism involving the Hippo signaling pathway.
Conclusions:
- KHKI-01128 and KHKI-01215 are potent and effective inhibitors of NUAK2.
- These compounds exhibit significant anticancer properties, including the suppression of proliferation and induction of apoptosis.
- The findings suggest that KHKI-01128 and KHKI-01215 hold considerable promise for pharmaceutical development in cancer treatment.
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