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

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 <b>2</b>, which contains a (<i>S</i>)-2-phenylglycinol structure as a key fragment to inhibit EGFR. However, compound <b>2</b> showed high clearance and poor oral bioavailability in its pharmacokinetics studies. In this work, we optimized compound <b>2</b> by scaffold hopping and exploiting the potent inhibitory activity of various warhead groups to obtain a clinical candidate, <b>78</b> (DBPR112), which not only displayed a potent inhibitory activity against EGFR^L858R/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 <i>F</i> = 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.