Discovery of an Oleanolic Acid/Hederagenin-Nitric Oxide Donor Hybrid as an EGFR Tyrosine Kinase Inhibitor for Non-Small-Cell Lung Cancer

  • J Nat Prod. 2019 Nov 22;82(11):3065-3073. doi: 10.1021/acs.jnatprod.9b00659.
Zhong Chen  1 ,  Kuo-Yen Huang  2  3 ,  Yong Ling  4 ,  Masuo Goto  5 ,  Hua-Qing Duan  1 ,  Xiao-Hang Tong  1 ,  Yan-Li Liu  1 ,  Yung-Yi Cheng  5 ,  Susan L Morris-Natschke  5 ,  Pan-Chyr Yang  6 ,  Shi-Lin Yang  1 ,  Kuo-Hsiung Lee  5  7
Affiliations
  • 1. College of Pharmaceutical Sciences , Soochow University , Suzhou 215123 , People's Republic of China.
  • 2. Institute of Biomedical Sciences , Academia Sinica , Taipei 11529 , Taiwan.
  • 3. Graduate Institute of Health Industry Technology and Research Center for Industry of Human Ecology , Chang Gung University of Science and Technology , Taoyuan 33303 , Taiwan.
  • 4. School of Pharmacy and Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target , Nantong University , Nantong 226001 , People's Republic of China.
  • 5. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy , University of North Carolina , Chapel Hill , North Carolina 27599-7369 , United States.
  • 6. Department of Internal Medicine , College of Medicine, National Taiwan University , Taipei 10617 , Taiwan.
  • 7. Chinese Medicine Research and Development Center , China Medical University and Hospital , Taichung 40447 , Taiwan.
PMID: 31718182 DOI: 10.1021/acs.jnatprod.9b00659
Abstract

Natural triterpenoids, such as oleanolic acid (OA) and hederagenin, display anti-lung Cancer effects, and nitric oxide (NO) is associated with some oncogenic signaling pathways. Accordingly, 17 OA/hederagenin-NO donor hybrids were designed, synthesized, and evaluated against tumor cells. The most potent compound, 13, significantly inhibited the proliferation of five tumor cell lines (IC50 4.6-5.2 μM), while hederagenin inhibited the growth of only A549 tumor cells (IC50 > 10 μM). Furthermore, compound 13 showed stronger inhibitory effects on EGFR-LTC kinase activity (IC50 0.01 μM) than hederagenin (IC50 > 20 μM) and inhibited the proliferation of gefitinib-resistant H1975 (IC50 8.1 μM) and osimertinib-resistant H1975-LTC (IC50 7.6 μM) non-small-cell lung Cancer (NSCLC) cells. Moreover, compound 13 produced the most NO in H1975 tumor cells, which indicated that NO may play a synergistic role. Collectively, compound 13, a novel hederagenin-NO donor hybrid with a different chemical structure from those of the current FDA-approved EGFR-targeted anti-NSCLC drugs, may be a promising lead compound for the treatment of NSCLC expressing gefitinib-resistant EGFR with a T790 M mutation or osimertinib-resistant EGFR-LTC with an L858R/T790M/C797S mutation. This work should shed light on the discovery of new anti-NSCLC drugs targeting EGFR from natural products.