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

Shu Yu Lin, Yung Chang Hsu, Yi Hui Peng, Yi Yu Ke, Wen Hsing Lin, Hsu Yi Sun, Hui Yi Shiao, Fu Ming Kuo, Pei Yi Chen, Tzu Wen Lien, Chun Hwa Chen, Chang Ying Chu, Sing Yi Wang, Kai Chia Yeh, Ching Ping Chen, Tsu An Hsu, Su Ying Wu, Teng Kuang Yeh, Chiung Tong Chen, Hsing Pang Hsieh

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2 引文 斯高帕斯(Scopus)

摘要

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.

原文English
頁(從 - 到)10108-10123
頁數16
期刊Journal of Medicinal Chemistry
62
發行號22
DOIs
出版狀態Published - 2019 十一月 27

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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