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Updated: May 6, 2026
A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
Rational Design, Synthesis, and Biological Evaluation of Novel c-Met Degraders for Lung Cancer Therapy
Xingyang Qiu1, Qingquan Zheng1, Dongdong Luo1
1Center for Molecular Oncology, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, 610064 Chengdu, China.
Abstract:
Cellular-mesenchymal epithelial transition factor (c-Met) is an attractive target for treating multiple cancers. Despite plentiful c-Met inhibitors have been developed, some issues, including the acquired drug resistance to c-Met inhibitors, have emerged to hamper their application in clinical treatment. Degradation of c-Met offers an opportunity to solve these issues. In this study, we developed a series of c-Met degraders, and the optimal compound 22b can efficiently degrade c-Met with a DC50 value of 0.59 nM in EBC-1 cells. Mechanistic studies revealed that compound 22b induced c-Met degradation via proteasome-mediated pathway. In addition, compound 22b suppressed the proliferation and also induced apoptosis of EBC-1 cells, outperforming the corresponding inhibitor tepotinib. Importantly, compound 22b showed favorable pharmacokinetic properties and significantly induced tumor regression in a xenograft model without obvious toxicity. In brief, this study provided compound 22b as a novel c-Met degrader for lung cancer therapy.
Insights
A novel compound, 22b, effectively degrades cellular-mesenchymal epithelial transition factor (c-Met) by targeting the proteasome pathway. This c-Met degrader shows promise for lung cancer therapy, outperforming existing inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Cellular-mesenchymal epithelial transition factor (c-Met) is a key target in cancer therapy.
- Acquired resistance to c-Met inhibitors limits their clinical efficacy.
- Targeting c-Met degradation presents a potential strategy to overcome resistance.
Purpose of the Study:
- To develop novel c-Met degraders.
- To evaluate the efficacy and mechanism of action of a lead compound, 22b.
- To assess the therapeutic potential of compound 22b in preclinical cancer models.
Main Methods:
- Synthesis and screening of c-Met degraders.
- Assessment of c-Met degradation using DC50 values in EBC-1 cells.
- Mechanistic studies involving proteasome-mediated pathways.
- In vitro proliferation and apoptosis assays.
- Pharmacokinetic studies and in vivo efficacy evaluation in xenograft models.
Main Results:
- Compound 22b demonstrated potent c-Met degradation with a DC50 of 0.59 nM.
- 22b induced c-Met degradation via the proteasome pathway.
- 22b suppressed cancer cell proliferation and induced apoptosis, outperforming tepotinib.
- Compound 22b exhibited favorable pharmacokinetics and significant tumor regression in vivo with minimal toxicity.
Conclusions:
- Compound 22b is a potent novel c-Met degrader.
- 22b offers a promising therapeutic strategy for lung cancer, potentially overcoming resistance to c-Met inhibitors.
- Further development of 22b for lung cancer therapy is warranted.
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