Structure-Guided Discovery of Potent, Selective, and Orally Bioavailable Werner Syndrome RecQ Helicase Inhibitors for the Treatment of Microsatellite Instability-High Tumors

  • J Med Chem. 2026 Jun 25;69(12):14492-14512. doi: 10.1021/acs.jmedchem.6c00331.
Qibang Sui  1  2 ,  Dan Wang  3 ,  Hui Hou  1  2 ,  Chen Shi  3 ,  Xiaoying Cai  1  4  5 ,  Yuanyang Zhou  1  6  7 ,  Rongrong Cui  1  5 ,  Manjia Li  3 ,  Jia Liu  3 ,  Dan Teng  1  5 ,  Chong Qin  2  8  9 ,  Sulin Zhang  1  4  5 ,  Mingyue Zheng  1  3  4  5
Affiliations
  • 1. Drug Discovery and Design Center, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China.
  • 2. Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, Shandong266003, China.
  • 3. School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing210023, China.
  • 4. School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou310024, China.
  • 5. University of Chinese Academy of Sciences, Beijing100049, China.
  • 6. School of Life Science and Technology, ShanghaiTech University, Shanghai201210, China.
  • 7. Lingang Laboratory, Shanghai200031, China.
  • 8. Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, 266003Shandong ,China.
  • 9. Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao266003, China.
PMID: 42234810 DOI: 10.1021/acs.jmedchem.6c00331
Abstract

Despite recent advances in immunotherapy for microsatellite instability-high (MSI-H) tumors, challenges of resistance persist, necessitating alternative therapeutic approaches. The synthetic lethal interaction between WRN helicase inhibition and MSI status presents a promising therapeutic strategy. Guided by the key structural features of the WRN-HRO761 complex, we rationally designed two classes of WRN inhibitors─spirocyclic compounds and benzo-fused heterocyclic analogs─by targeting the solvent-exposed region. Among these, Q15 exhibited potent in vitro activity and excellent cellular selectivity. Compared with HRO761 in vivo, Q15 demonstrated more favorable oral pharmacokinetic properties and superior antitumor efficacy at 10 mg/kg, comparable efficacy at 20 mg/kg, and achieved complete tumor regression at 40 mg/kg. Preliminary safety evaluation further indicated that Q15 possesses a favorable safety profile. These findings support Q15 as a promising WRN inhibitor candidate for the treatment of MSI-H tumors.

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