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Poster Display session 3

1597 - Discovery of Clinical Candidate DBPR112, a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor for the Treatment of Non-Small Cell Lung Cancer


30 Sep 2019


Poster Display session 3


Translational Research

Tumour Site

Non-Small Cell Lung Cancer


Hsing-pang Hsieh


Annals of Oncology (2019) 30 (suppl_5): v760-v796. 10.1093/annonc/mdz268


H. Hsieh1, J. Chang2, C. Yeh3, S. Lin1, Y. Ke1, W. Lin1, T. Hsu1, S. Wu1, T. Yeh1

Author affiliations

  • 1 Biotechnology And Pharmaceutical Research, National Health Research Institutes - Zhunan Campus, 35053 - Zhunan/TW
  • 2 College Of Medicine, National Cheng Kung University, 701 - Tainan/TW
  • 3 Liver Research Center, Chang Gung Medical Foundation - Linkou Chang Gung Memorial Hospital, 33305 - Taoyuan City/TW


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Abstract 1597


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.


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.


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.


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.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

The authors.


National Health Research Institutes, Taiwan.


All authors have declared no conflicts of interest.

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