Identification of a new inhibitor of KRAS-PDEδ interaction targeting KRAS mutant nonsmall cell lung cancer

  • Int J Cancer. 2019 Sep 1;145(5):1334-1345. doi: 10.1002/ijc.32222.
Elaine Lai-Han Leung  1  2 ,  Lian Xiang Luo  1 ,  Ying Li  1 ,  Zhong-Qiu Liu  3 ,  Lan Lan Li  4 ,  Dan Feng Shi  4 ,  Ying Xie  1 ,  Min Huang  5 ,  Lin Lin Lu  3 ,  Fu Gang Duan  1 ,  Ju Min Huang  1 ,  Xing Xing Fan  1 ,  Zhong Wen Yuan  1 ,  Jian Ding  5 ,  Xiao Jun Yao  1  4 ,  David C Ward  1 ,  Liang Liu  1
Affiliations
  • 1. State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute For Applied Research in Medicine and Health, Macau University of Science and Technology, Taipa, Macau (SAR), China.
  • 2. Department of Thoracic Surgery, State Key Laboratory of Respiratory Diseases, National Clinical Research Center for Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 3. International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 4. State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, China.
  • 5. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academic of Sciences, Shanghai, China.
PMID: 30786019 DOI: 10.1002/ijc.32222
Abstract

Oncogenic KRAS is considered a promising target for anti-cancer therapy. However, direct pharmacological strategies targeting KRAS-driven cancers remained unavailable. The prenyl-binding protein PDEδ, a transporter of KRAS, has been identified as a potential target for pharmacological inhibitor by selectively binding to its prenyl-binding pocket, impairing oncogenic KRAS signaling pathway. Here, we discovered a novel PDEδ inhibitor (E)-N'-((3-(tert-butyl)-2-hydroxy-6,7,8,9-tetrahydrodibenzo[b,dfuran-1-yl)methylene)-2,4-dihydroxybenzohydrazide(NHTD) by using a high-throughput docking-based virtual screening approach. In vitro and in vivo studies demonstrated that NHTD suppressed proliferation, induced Apoptosis and inhibited oncogenic K-Ras signaling pathways by disrupting KRAS-PDEδ interaction in nonsmall cell lung Cancer (NSCLC) harboring KRAS mutations. NHTD redistributed the localization of KRAS to endomembranes by targeting the prenyl-binding pocket of PDEδ and exhibited the suppression of abnormal KRAS function. Importantly, NHTD prevented tumor growth in xenograft and KRAS mutant mouse model, which presents an effective strategy targeting KRAS-driven Cancer.

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