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Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer
Shipeng He1, Junhui Ma2, Yuxin Fang2
1Institute of Translational Medicine, Shanghai University, Shanghai 200444, China.
Abstract:
The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment.
Insights
Researchers developed a novel homo-PROTAC strategy to degrade MDM2, a protein implicated in cancer. This approach shows promising in vivo antitumor activity, offering a potential new cancer therapy.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Oncology
Background:
- MDM2-P53 inhibitors face challenges due to dose-related adverse effects, limiting their use as safe anticancer agents.
- MDM2 plays a dual role as an E3 ubiquitin ligase and a binder to the tumor suppressor P53.
- Disrupting the MDM2-P53 interaction is a key strategy for cancer therapy.
Purpose of the Study:
- To develop a novel homo-PROTAC strategy for targeted self-degradation of MDM2.
- To investigate the efficacy of homo-PROTACs in disrupting the MDM2-P53 interaction.
- To evaluate the in vivo therapeutic potential of the developed homo-PROTACs.
Main Methods:
- Design and synthesis of novel homo-PROTACs targeting MDM2.
- Assessment of MDM2 dimerization and self-degradation in A549 non-small cell lung cancer cells.
- Evaluation of in vivo antitumor activity using an A549 xenograft nude mouse model.
Main Results:
- PROTAC 11a demonstrated efficient dimerization of MDM2 and induced proteasome-dependent self-degradation in cancer cells.
- Enantiomer 11a-1 exhibited significant in vivo antitumor activity in a preclinical mouse model.
- This marks the first demonstration of in vivo therapeutic potency for a homo-PROTAC.
Conclusions:
- Homo-PROTACs represent a viable strategy for targeted MDM2 knockdown.
- The developed homo-PROTACs hold potential as a new class of safe and effective cancer therapeutics.
- Further development of homo-PROTACs could lead to novel treatments for cancers driven by MDM2 overexpression.
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