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

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.