Structure-Based Design of Potent and Highly Selective NUAK1 Inhibitors by Exploiting a Unique Glutamate Switch for
Shan Li1,2, Yingao Wang1,3, Xuechen Liu1,3
1Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
Abstract:
NUAK1, an AMPK-related kinase overexpressed in cancers, plays a crucial role in tumor metastasis and cell survival, making it an attractive cancer therapeutic target. Herein, we report potent, selective NUAK1 inhibitors via structure-guided repurposing of a covalent JAK3 inhibitor. By capitalizing on the critical structural difference─Cys909 in JAK3 versus Glu139 in NUAK1─we substituted the electrophilic warhead with glutamate-favoring moieties, a modification that confers selective NUAK1 targeting. Supporting this design rationale, cocrystal structures verify the specific engagement of these moieties with the Glu139 residue of NUAK1. Among the synthesized analogs, candidate compound 10i exhibits subnanomolar NUAK1 inhibition (IC50 = 0.49 nM) and kinome-wide selectivity. Besides, 10i suppresses proliferation, migration, and invasion of triple-negative breast cancer cells, reverses EMT markers, and shows robust antitumor efficacy in mouse xenografts. This study provides a promising lead and validates Glu139 as an anchor for selective NUAK1 targeting.
Insights
Researchers developed novel NUAK1 inhibitors by modifying a JAK3 inhibitor. These compounds target cancer metastasis and survival, with one potent inhibitor showing significant efficacy in preclinical models.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- NUAK1 (AMPK-related kinase) is overexpressed in cancers and promotes tumor metastasis and survival.
- This makes NUAK1 a significant target for cancer therapeutics.
Purpose of the Study:
- To develop potent and selective inhibitors of NUAK1.
- To leverage structure-guided drug design by repurposing a covalent JAK3 inhibitor.
Main Methods:
- Structure-guided repurposing of a covalent JAK3 inhibitor.
- Modification of the inhibitor's warhead to favor interaction with NUAK1's Glu139 residue.
- Synthesis and evaluation of novel NUAK1 inhibitors, including cocrystallography and in vitro/in vivo assays.
Main Results:
- A novel series of selective NUAK1 inhibitors were identified.
- Compound 10i demonstrated subnanomolar NUAK1 inhibition (IC50 = 0.49 nM) with high kinome selectivity.
- Compound 10i suppressed triple-negative breast cancer cell proliferation, migration, and invasion, reversed EMT markers, and showed antitumor efficacy in mouse xenografts.
Conclusions:
- The study successfully developed potent and selective NUAK1 inhibitors through structure-guided design.
- The findings validate Glu139 as a key residue for selective NUAK1 targeting.
- Compound 10i represents a promising lead for NUAK1-targeted cancer therapy.
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