Structure‐Informed Design of Distinct Parallel G‐Quadruplex Stabilizers for <i>KRAS</i> ‐Driven Cancer Therapy
Abstract
ABSTRACT Targeting oncogene promoter G‐quadruplexes (G4s) is a compelling therapeutic strategy against human malignancies. However, clinical progress has been hindered by the lack of potent and structurally diverse G4‐targeting ligands. Herein, using parallel KRAS proximal promoter G4 ( KRAS ‐G4) as a model system, we screened an in‐house natural product library and identified dehydroevodiamine (DEE) as a novel G4 stabilizer. Although DEE showed only modest anticancer activity, structural analyses determined its predominant binding mode to KRAS ‐G4. Leveraging these structural insights, we rationally designed and synthesized 15 DEE analogues. Among them, compound 7i emerged as the lead candidate, demonstrating a 9‐fold higher binding affinity and up to 20‐fold improvement in antiproliferative activity over DEE. We further determined the high‐resolution NMR structure of the KRAS ‐G4– 7i complex, uncovering a distinct dual‐binding mode, featuring extensive π–π stacking interactions with outer G‐tetrads and specific hydrogen bonding within groove regions. Functional analysis showed 7i effectively suppressed transcription of several G4‐containing oncogenes, induced genome‐wide G4 formation, and triggered DNA damage in colorectal cancer cells. Moreover, 7i significantly inhibited the growth of patient‐derived colorectal tumor organoids. Overall, our findings establish a structural framework for rational design of parallel G4‐targeting ligands and emphasize an alternative G4‐based therapeutic strategy for KRAS ‐driven cancers.
Article Details
Authors (16)
Lulu Zhang
Kang Han
Xiaozhe Wang
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China
Xiaolin Yu
China-Russia Belt and Road Joint Laboratory for Intelligent Chemistry and Advanced Materials of Liaoning Province, School of Chemistry
Yongqiang Zhang
Sihan He
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China
Zhiwei Han
Yushuang Liu
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China
Jun‐Cheng Su
Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China) School of Chemistry and Pharmaceutical Sciences Guangxi Normal University Guilin People's Republic of China
Jun Zhou
Shengen Yi
Department of General Surgery The Second Xiang Ya Hospital of Central South University Changsha People's Republic of China
Shengtao Xu
State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University
Jinlei Bian
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China
Kewei Zheng
Xiangtan Central Hospital/Affiliated Hospital of Hunan University School of Biomedical Sciences Hunan University Changsha People's Republic of China
Ling‐Yi Kong
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China
Kai‐Bo Wang
State Key Laboratory of Natural Medicines Basic Medical Research Innovation Center for Anti‐Cancer Drugs (Ministry of Education of China) and Jiangsu Key Laboratory of Bioactive Natural Product Research China Pharmaceutical University Nanjing People's Republic of China