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

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

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.

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