Discovery of a prominent dual-target DDR1/EGFR inhibitor aimed DDR1/EGFR-positive NSCLC.
Bioorg Chem
; 149: 107500, 2024 Aug.
Article
in En
| MEDLINE
| ID: mdl-38823310
ABSTRACT
This study aimed to develop the first dual-target small molecule inhibitor concurrently targeting Discoidin domain receptor 1 (DDR1) and Epidermal growth factor receptor (EGFR), which play a crucial interdependent roles in non-small cell lung cancer (NSCLC), demonstrating a synergistic inhibitory effect. A series of innovative dual-target inhibitors for DDR1 and EGFR were discovered. These compounds were designed and synthesized using structural optimization strategies based on the lead compound BZF02, employing 4,6-pyrimidine diamine as the core scaffold, followed by an investigation of their biological activities. Among these compounds, D06 was selected and showed micromolar enzymatic potencies against DDR1 and EGFR. Subsequently, compound D06 was observed to inhibit NSCLC cell proliferation and invasion. Demonstrating acceptable pharmacokinetic performance, compound D06 exhibited its anti-tumor activity in NSCLC PC-9/GR xenograft models without apparent toxicity or significant weight loss. These collective results showcase the successful synthesis of a potent dual-targeted inhibitor, suggesting the potential therapeutic efficacy of co-targeting DDR1 and EGFR for DDR1/EGFR-positive NSCLC.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Drug Screening Assays, Antitumor
/
Carcinoma, Non-Small-Cell Lung
/
Protein Kinase Inhibitors
/
Cell Proliferation
/
Dose-Response Relationship, Drug
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ErbB Receptors
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Discoidin Domain Receptor 1
/
Lung Neoplasms
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Bioorg Chem
Year:
2024
Document type:
Article
Affiliation country:
China