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Discovery of a Furanopyrimidine-based Epidermal Growth Factor Receptor Inhibitor (DBPR112) as a Clinical Candidate for the Treatment of Non-small Cell Lung Cancer
S.-Y. Lin, Y. C. Hsu, Y.-H. Peng, Y.-Y. Ke, W.-H. Lin, H.-Y. Sun, H.-Y. Shiao, F.-M. Kuo, P.-Y. Chen, T.-W. Lien, C.-H. Chen, C.-Y. Chu, S.-Y. Wang, K.-C. Yeh, C.-P. Chen, T.-A. Hsu, S.-Y. Wu, T.-K. Yeh, C.-T. Chen, and H.-P. Hsieh*
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.