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
  • 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.

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