Related Experiment Video
Updated: Jan 11, 2026
Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids
Published on: November 22, 2021
Design, synthesis and structure-activity relationship analysis of dibenzodiazepinone derivatives against Osimertinib
Chengliu Jin1, Zhen Zhang1, Peng Liao1
1School of Chemistry and Chemical Engineering, Guangdong Cosmetics Engineering & Technology Research Center, Guangdong Pharmaceutical University Zhongshan 528458 P. R. China.
Abstract:
Lung cancer, particularly NSCLC, is the leading cause of cancer-related deaths worldwide, accounting for over 80% of cases. Mutations in the epidermal growth factor receptor (EGFR) are key drivers of NSCLC. Although three generations of EGFR tyrosine kinase inhibitors (TKIs) have been developed, resistance limits their efficacy. The dibenzodiazepinone scaffold exhibits diverse biological activities, however, reports on its derivatives for treating NSCLC with EGFR mutations, particularly triple mutations, are rare. Guided by the binding model of DDC4002 with EGFRT790M/V948R, this study synthesized and characterized 36 dibenzodiazepinone analogues, evaluating their antiproliferative activity against NSCLC cell lines. Structure-activity relationship analysis highlighted the importance of substituents at the C2 and N10 positions. Compound 33 exhibited the strongest inhibitory effects, especially for H1975™ cells (EGFRL858R/T790M/C797S) with a 2.4-fold lower IC50 (2.7 μM) than osimertinib (6.5 μM). It effectively inhibited colony formation, migration of H1975™ cells, induced G0/G1 arrest, and promoted apoptosis through suppressing EGFR and AKT phosphorylation. These findings demonstrate the potential of optimizing the dibenzodiazepinone framework for developing novel potent molecules against osimertinib resistant NSCLC cells, providing valuable insights for future research.
Insights
New dibenzodiazepinone compounds show promise against non-small cell lung cancer (NSCLC) with EGFR mutations. Compound 33 effectively targets osimertinib-resistant cells, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality worldwide.
- Epidermal growth factor receptor (EGFR) mutations drive NSCLC, and resistance to EGFR tyrosine kinase inhibitors (TKIs) limits treatment efficacy.
- The dibenzodiazepinone scaffold has shown biological activity, but its derivatives for treating EGFR-mutated NSCLC, especially triple mutations, are underexplored.
Purpose of the Study:
- To synthesize and evaluate novel dibenzodiazepinone analogues as potential therapeutics for NSCLC with EGFR mutations.
- To identify potent compounds effective against osimertinib-resistant NSCLC cell lines.
- To elucidate the structure-activity relationships (SAR) of these novel compounds.
Main Methods:
- Synthesis and characterization of 36 dibenzodiazepinone analogues.
- Antiproliferative activity assessment against NSCLC cell lines.
- Structure-activity relationship analysis focusing on C2 and N10 substituents.
- In vitro assays including colony formation, migration, cell cycle arrest, apoptosis induction, and Western blotting for signaling pathway analysis.
Main Results:
- Compound 33 demonstrated significant antiproliferative activity against H1975™ cells (EGFRL858R/T790M/C797S), with a lower IC50 (2.7 μM) than osimertinib (6.5 μM).
- Compound 33 inhibited colony formation and migration, induced G0/G1 cell cycle arrest, and promoted apoptosis in H1975™ cells.
- Treatment with Compound 33 suppressed EGFR and AKT phosphorylation, indicating targeted pathway inhibition.
Conclusions:
- The dibenzodiazepinone framework can be optimized to develop potent molecules against osimertinib-resistant NSCLC.
- Compound 33 represents a promising lead candidate for novel NSCLC therapies targeting complex EGFR mutations.
- These findings provide valuable insights for future drug development against resistant lung cancer.
More Related Videos
Related Concept Videos
01:28Structure-Activity Relationships and Drug Design
SAR studies the intricate relationship between a drug's chemical structure and biological activity. It focuses on understanding how modifications to a drug's structure can influence...
01:16Adrenergic Agonists: Chemistry and Structure-Activity Relationship
Aromatic ring substitutions: Substituting the aromatic ring with –OH groups at positions 3 and 4 yields catecholamines (e.g., epinephrine), which have a high affinity for adrenoceptors. Hydrogen bonding between –OH groups and receptors enhances adrenergic activity.
Separation of...
01:22Direct-Acting Cholinergic Agonists: Chemistry and Structure-Activity Relationship
The direct-acting...
01:29Cholinergic Antagonists: Chemistry and Structure-Activity Relationship