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Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
Synthesis, and biological evaluation of EGFR/HER2-NAMPT conjugates for tumor treatment
Mengyuan Ding1, Qianqian Shen2, Wei Lu3
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, People's Republic of China.
Abstract:
Throughout the reported applications of EGFR inhibitors, it is usually employed with HDAC or other targets to design multi-target inhibitors for cancer treatment. In this paper, we designed a drug conjugate that targeted EGFR&HER2 and had inhibitory activity of NAMPT simultaneously. Compound 20c significantly inhibited the EGFR&HER2 and NAMPT enzyme activities, and had comparable or even higher anti-proliferative activity than lapatinib in various cancer cells with over-expressed EGFR and HER2. Importantly, 20c was expected to increase sensitivity to EGFR inhibitor-resistant cells. In Osimertinib-resistant cells (NCI-1975 cells with the L858R/T790M/C797S triple mutation and Ba/F3 cells with the Del19/T790M/C797S triple mutation), the anti-proliferative activity of compound 20c was increased by more than twofold compared with Osimertinib, so as to obtain better curative effect. This strategy is a promising method of embedding multiple pharmacophores into a single molecule, which lays a good foundation for the design and synthesis of small molecule drug conjugates with strong targeting ability and high cytotoxicity.
Insights
This study developed a novel drug conjugate targeting both EGFR/HER2 and NAMPT for cancer therapy. The compound demonstrated potent anti-cancer activity, even in resistant cell lines, offering a promising new treatment strategy.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Epidermal Growth Factor Receptor (EGFR) inhibitors are crucial in cancer treatment.
- Developing multi-target inhibitors is key to overcoming resistance and improving efficacy.
- Nicotinamide phosphoribosyltransferase (NAMPT) is an emerging cancer target.
Purpose of the Study:
- To design and synthesize a novel drug conjugate targeting EGFR, HER2, and NAMPT simultaneously.
- To evaluate the anti-proliferative activity of the designed compound against cancer cells.
- To assess the efficacy of the compound in overcoming EGFR inhibitor resistance.
Main Methods:
- Design and synthesis of a multi-target drug conjugate (Compound 20c).
- Enzyme inhibition assays for EGFR, HER2, and NAMPT.
- In vitro anti-proliferative assays in various cancer cell lines.
- Evaluation in Osimertinib-resistant cancer cell models.
Main Results:
- Compound 20c exhibited significant inhibition of EGFR, HER2, and NAMPT enzyme activities.
- It demonstrated comparable or superior anti-proliferative effects to lapatinib in EGFR/HER2-overexpressing cells.
- Compound 20c showed over twofold increased activity compared to Osimertinib in resistant cell lines.
Conclusions:
- The developed drug conjugate is a promising strategy for multi-targeted cancer therapy.
- Embedding multiple pharmacophores into a single molecule enhances targeting and cytotoxicity.
- This approach provides a foundation for novel small molecule drug conjugate development.
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