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Published on: September 30, 2016
Optimization of WZ4003 as NUAK inhibitors against human colorectal cancer
Huali Yang1, Xiaobing Wang2, Cheng Wang2
1Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, Department of Natural Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang, 110016, China.
Abstract:
NUAK, the member of AMPK (AMP-activated protein kinase) family of protein kinases, is phosphorylated and activated by the LKB1 (liver kinase B1) tumor suppressor protein kinase. Recent work has indicated that NUAK1 is a key component of the antioxidant stress response pathway, and the inhibition of NUAK1 will suppress the growth and survival of colorectal tumors. As a promising target for anticancer drugs, few inhibitors of NUAK were developed. With this goal in mind, based on NUAK inhibitor WZ4003, a series of derivatives has been synthesized and evaluated for anticancer activity. Compound 9q, a derivative of WZ4003 by removing a methoxy group, was found to be the most potential one with stronger inhibitory against NUAK1/2 enzyme activity, tumor cell proliferation and inducing apoptosis of tumor cells. By in vivo efficacy evaluations of colorectal SW480 xenografts, 9q suppresses tumor growth more effectively with an excellent safety profile in vivo and is therefore seen as a suitable candidate for further investigation.
Insights
Researchers developed a novel NUAK inhibitor, compound 9q, to target colorectal tumors. This compound effectively suppressed tumor growth and induced apoptosis, showing promise as an anticancer drug candidate with a good safety profile.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- NUAK1, part of the AMPK family, is activated by LKB1 and crucial for antioxidant stress response.
- NUAK1 inhibition shows potential in suppressing colorectal tumor growth and survival.
- Limited development of NUAK inhibitors presents a therapeutic gap.
Purpose of the Study:
- To synthesize and evaluate novel NUAK inhibitors based on WZ4003.
- To identify potent anticancer agents targeting NUAK1/2 for colorectal cancer treatment.
Main Methods:
- Synthesis of NUAK inhibitor derivatives based on WZ4003.
- In vitro evaluation of enzyme activity, tumor cell proliferation, and apoptosis induction.
- In vivo efficacy assessment in colorectal SW480 xenograft models.
Main Results:
- Compound 9q, a WZ4003 derivative, demonstrated superior inhibitory activity against NUAK1/2.
- 9q effectively suppressed tumor cell proliferation and induced apoptosis in vitro.
- In vivo studies showed 9q significantly suppressed colorectal tumor growth with a favorable safety profile.
Conclusions:
- Compound 9q is a highly promising candidate for colorectal cancer therapy.
- Further investigation of 9q is warranted due to its potent anticancer activity and safety.
- Targeting NUAK offers a viable strategy for developing new colorectal cancer treatments.
