2. Academic Validation
  3. Structure-Based Design of Potent and Highly Selective NUAK1 Inhibitors by Exploiting a Unique Glutamate Switch for the Prevention of Tumor Growth, Migration, and Invasion

Structure-Based Design of Potent and Highly Selective NUAK1 Inhibitors by Exploiting a Unique Glutamate Switch for the Prevention of Tumor Growth, Migration, and Invasion

  • J Med Chem. 2026 Apr 9;69(7):7817-7838. doi: 10.1021/acs.jmedchem.5c03079.
Shan Li 1 2,  Yingao Wang 1 3,  Xuechen Liu 1 3,  Hong Zhang 4,  Chong Lei 5,  Zhen Wang 5,  Yuqing Zhang 1,  Xiaoli Du 1,  Lingrui Xu 1 3,  Ziwen Li 1 3,  Yuyan Shi 1 3,  Xinpeng Ning 1 3,  Ji Cao 6,  Zhi-Min Zhang 4,  Dawei Ma 1 5,  Ke Ding 4 5
Affiliations

Affiliations

  • 1 Hangzhou Institute of Medicine, Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China.
  • 2 Zhejiang Cancer Hospital, Hangzhou, Zhejiang 310022, China.
  • 3 School of Molecular Medicine, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China.
  • 4 School of Pharmacy, Jinan University, Guangzhou 510632, China.
  • 5 Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 20032, China.
  • 6 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China.
PMID: 41855469 DOI: 10.1021/acs.jmedchem.5c03079
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.

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