English  |  正體中文  |  简体中文  |  Items with full text/Total items : 12145/12927 (94%)
Visitors : 848677      Online Users : 1245
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
Scope Tips:
  • please add "double quotation mark" for query phrases to get precise results
  • please goto advance search for comprehansive author search
    •  Adv. Search
    Home ‧ Login ‧ Upload ‧ Help ‧ About ‧ Administer Goto mobile version


    Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/12298


    Title: Discovery of clinical candidate DBPR112, a furanopyrimidine-based epidermal growth factor receptor inhibitor for the treatment of non-small cell lung cancer
    Authors: Hsieh, HP;Chang, JY;Yeh, CT;Lin, SY;Ke, YY;Lin, WH;Hsu, TA;Wu, SY;Yeh, TK
    Contributors: Institute of Biotechnology and Pharmaceutical Research
    Abstract: Background: Lung cancer has the highest rate of morbidity and mortality among various cancer types, being responsible for over 1.69 million deaths per year. Approximately 80–85% of the lung cancer patients diagnosed present non-small cell lung cancer (NSCLC), while 10–15% present small cell lung cancer (SCLC). Mutations in the epidermal growth factor receptor (EGFR) have been observed in ∼50% of patients, in particular, in East Asian NSCLC patients. The single-point mutation L858R (exon 21) and amino acids deletions in the tyrosine kinase (TK) domain (exon 19) constitute 90% of all EGFR-activating mutations. Methods: We introduced an acrylamide group as a Michael acceptor, resulting in compound 2, which showed potent in vitroactivity in both wild and mutant EGFR kinases and potent anti-proliferative activity in HCC827 lung cancer cell line. In this work, we apply SBDD to guide the optimization of lead compound 2and perform a detailed structure-activity relationship (SAR) study to bring this drug candidate into the next development stage. Results: We optimized the compound 2by scaffold hopping and by exploiting the potent inhibitory activity of various warhead groups. The results of the multi-objective optimization obtained the clinical candidate, compound 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFR L858R/T790M double mutations, but also exhibited 10-fold potency better than 3rd generation inhibitor, osimertinib, against three EGFR and one HER2 exon 20 insertion mutations, since there are currently no EGFR-directed therapies approved specifically for the treatment of this mutation. Conclusions: X-ray co-crystal study of EGFRWTKinase and compound 78 revealed the potential of future design for mutant-selective inhibitors. Finally, furanopyrimidine 78 was selected as a clinical candidate to conduct all preclinical experiments and is currently undergoing phase 1 clinical trial in Taiwan.
    Date: 2019-10
    Relation: Annals of Oncology. 2019 Oct;30(Suppl. 5):789.
    Link to: https://doi.org/10.1093/annonc/mdz268.089
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000491295505228
    Appears in Collections:[葉燈光] 會議論文/會議摘要
    [伍素瑩] 會議論文/會議摘要
    [徐祖安] 會議論文/會議摘要
    [謝興邦] 會議論文/會議摘要
    [林書玉] 會議論文/會議摘要

    Files in This Item:

    File Description SizeFormat
    ISI000491295505228.pdf77KbAdobe PDF335View/Open


    All items in NHRI are protected by copyright, with all rights reserved.

    Related Items in TAIR

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - Feedback