2. Academic Validation
  3. Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer

Discovery of a Furanopyrimidine-Based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-Small Cell Lung Cancer

  • J Med Chem. 2019 Nov 27;62(22):10108-10123. doi: 10.1021/acs.jmedchem.9b00722.
Shu-Yu Lin 1,  Yung Chang Hsu 1,  Yi-Hui Peng 1,  Yi-Yu Ke 1,  Wen-Hsing Lin 1,  Hsu-Yi Sun 1,  Hui-Yi Shiao 1,  Fu-Ming Kuo 1,  Pei-Yi Chen 1,  Tzu-Wen Lien 1,  Chun-Hwa Chen 1,  Chang-Ying Chu 1,  Sing-Yi Wang 1,  Kai-Chia Yeh 1,  Ching-Ping Chen 1,  Tsu-An Hsu 1,  Su-Ying Wu 1,  Teng-Kuang Yeh 1,  Chiung-Tong Chen 1,  Hsing-Pang Hsieh 1 2
Affiliations

Affiliations

  • 1 Institute of Biotechnology and Pharmaceutical Research , National Health Research Institutes , 35 Keyan Road , Zhunan, Miaoli County 35053 , Taiwan , ROC.
  • 2 Department of Chemistry , National Tsing Hua University , Hsinchu 30013 , Taiwan , ROC.
PMID: 31560541 DOI: 10.1021/acs.jmedchem.9b00722
Abstract

Epidermal growth factor receptor (EGFR)-targeted therapy in non-small cell lung Cancer represents a breakthrough in the field of precision medicine. Previously, we have identified a lead compound, furanopyrimidine 2, which contains a (S)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound 2 showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound 2 by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, 78 (DBPR112), which not only displayed a potent inhibitory activity against EGFRL858R/T790M double mutations but also exhibited tenfold potency better than the third-generation inhibitor, osimertinib, against EGFR and HER2 exon 20 insertion mutations. Overall, pharmacokinetic improvement through lead-to-candidate optimization yielded fourfold oral AUC better that afatinib along with F = 41.5%, an encouraging safety profile, and significant antitumor efficacy in in vivo xenograft models. DBPR112 is currently undergoing phase 1 clinical trial in Taiwan.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128778
    98.37%, EGFR 抑制剂
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