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 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.

• Authors: 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
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 62 Issue 22 Pg. 10108-10123 (11 27 2019) ISSN: 1520-4804 [Electronic] United States
• PMID: 31560541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• Pyrimidines
• EGFR protein, human
• ERBB2 protein, human
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Animals
• Antineoplastic Agents (chemistry, metabolism, pharmacology)
• Binding Sites
• Carcinoma, Non-Small-Cell Lung (drug therapy)
• Cell Line, Tumor
• Crystallography, X-Ray
• Drug Design
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors, chemistry, genetics, metabolism)
• Exons
• Humans
• Lung Neoplasms (drug therapy)
• Male
• Mice, Inbred ICR
• Mice, Nude
• Mutation
• Protein Kinase Inhibitors (chemistry, metabolism, pharmacology)
• Pyrimidines (chemistry)
• Rats
• Receptor, ErbB-2
• Structure-Activity Relationship
• Xenograft Model Antitumor Assays