國家衛生研究院 NHRI:Item 3990099045/8770
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    题名: Novel irreversible EGFR tyrosine kinase inhibitor, DBPR112, as a therapeutic candidate for lung adenocarcinoma
    作者: Shiao, HY;Hsu, TA;Lin, WH;Yang, TT;Hsieh, HF;Chen, CT;Yeh, TK;Hsieh, HP
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Lung cancer is the leading cause of cancer death in the world and non-small cell lung cancer (NSCLC) accounts for 85% of the lung cancer deaths. In recent years, EGFR tyrosine kinase inhibitors (TKIs) have showed remarkable effects in patients with certain genetic alternations in the EGFR proteins. However, the clinical benefits of two first-generation EGFR TKIs (gefitinib and erlotinib) have been limited due to the acquired resistance from patients within 9-12 months after treatment, therefore, the discovery of next-generation EGFR-TKIs poses an utmost priority. Our team at IBPR has identified DBPR112 as a potent EGFR-TKI, showing IC50 of 2 nM in HCC827 cells, EGFRWild-Type (IC50: 10 nM) and EGFRL858R/T790M (IC50: 70 nM), which are comparatively better than gefitinib and similar to that of BIBW2992 (afatinib, developed by Boehringer Ingelheim, and approved by FDA in 2013). DBPR112 (10, 50 and 100 mg/kg/day, 5 days/wk for 2 weeks) was orally effective against the growth of human lung HCC827 tumors subcutaneously xenografted in nude mice. A dramatic reduction in tumor size was noted with DBPR112 treatment at 50 and 100 mg/kg/day, while displaying negligible body weight loss in all dosing groups. In addition, the pharmacokinetics properties of DBPR112 are superior to those of BIBW2992; demonstrating the potential of DBPR112 as a therapeutic candidate for the treatment of lung adenocarcinoma with EGFR mutations. This NRPB-granted 4-year top-down project was commenced in Dec. 2012 and aimed at accomplishing a comprehensive program of pre-clinical development and phase I study. To date, several pre-clinical studies and progress were steadily accomplished, including non-GMP production of 5 kg DBPR112 (tox-lot), preliminary analysis methods development, pre-formulation study, pharmacokinetics/metabolism studies and preliminary toxicology evaluation. GLP-toxicity studies, GMP-production of DBPR112 (clinical-lot) and formulation for clinical use will be scheduled in 2014 (2nd year of this top-down project), and we look forward to filing an IND application in early 2015.
    日期: 2014-10
    關聯: Cancer Research. 2014 Oct;74(19 Suppl.):Abstract No. 1756.
    Link to: http://dx.doi.org/10.1158/1538-7445.am2014-1756
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0008-5472&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000349906901477
    显示于类别:[謝興邦] 會議論文/會議摘要
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