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Published on: May 15, 2019
A novel FAK-degrading PROTAC molecule exhibited both anti-tumor activities and efficient MDR reversal effects
Ming-Shi Xu1, Xiao-Fan Gu1, Cong Li1
1Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200062, China.
Abstract:
FAK (focal adhesion kinase) is widely involved in cancer growth and drug resistance development. Thus, FAK inhibition has emerged as an effective strategy for tumor treatment both as a monotherapy or in combination with other treatments. But the current FAK inhibitors mainly concentrate on its kinase activity, overlooking the potential significance of FAK scaffold proteins. In this study we employed the PROTAC technology, and designed a novel PROTAC molecule F2 targeting FAK based on the FAK inhibitor IN10018. F2 exhibited potent inhibitory activities against 4T1, MDA-MB-231, MDA-MB-468 and MDA-MB-435 cells with IC50 values of 0.73, 1.09, 5.84 and 3.05 μM, respectively. On the other hand, F2 also remarkably reversed the multidrug resistance (MDR) in HCT8/T, A549/T and MCF-7/ADR cells. Both the effects of F2 were stronger than the FAK inhibitor IN10018. To our knowledge, F2 was the first reported FAK-targeted PROTAC molecule exhibiting reversing effects on chemotherapeutic drug resistance, and its highest reversal fold could reach 158 times. The anti-tumor and MDR-reversing effects of F2 might be based on its inhibition on AKT (protein kinase B, PKB) and ERK (extracellular signal-regulated kinase) signaling pathways, as well as its impact on EMT (epithelial-mesenchymal transition). Furthermore, we found that F2 could reduce the protein level of P-gp in HCT8/T cells, thereby contributing to reverse drug resistance from another perspective. Our results will boost confidence in future research focusing on targeting FAK and encourage further investigation of PROTAC with potent in vivo effects.
Insights
A novel PROTAC molecule, F2, effectively inhibits cancer cell growth and reverses multidrug resistance by targeting FAK (focal adhesion kinase). This FAK-targeted PROTAC molecule shows promise for overcoming drug resistance in cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Focal adhesion kinase (FAK) plays a crucial role in cancer progression and the development of drug resistance.
- Existing FAK inhibitors primarily target kinase activity, neglecting the importance of FAK as a scaffold protein.
- Targeting FAK offers a potential therapeutic strategy for cancer, either alone or in combination treatments.
Purpose of the Study:
- To design and evaluate a novel PROTAC (proteolysis-targeting chimera) molecule targeting FAK.
- To assess the efficacy of the FAK-targeted PROTAC in inhibiting cancer cell proliferation and reversing multidrug resistance (MDR).
- To investigate the underlying mechanisms of the PROTAC's anti-tumor and MDR-reversing effects.
Main Methods:
- Design of a novel FAK-targeted PROTAC molecule, F2, based on the FAK inhibitor IN10018 using PROTAC technology.
- Evaluation of F2's inhibitory activity against various cancer cell lines (4T1, MDA-MB-231, MDA-MB-468, MDA-MB-435).
- Assessment of F2's ability to reverse multidrug resistance in resistant cell lines (HCT8/T, A549/T, MCF-7/ADR) and investigation of its effects on signaling pathways (AKT, ERK) and EMT.
Main Results:
- F2 demonstrated potent inhibition of cancer cell growth with low IC50 values across multiple cell lines.
- F2 significantly reversed multidrug resistance in resistant cancer cells, with effects superior to the parent inhibitor IN10018.
- The highest reversal fold for MDR reached 158 times, indicating substantial efficacy.
- F2's anti-tumor and MDR-reversing effects are potentially mediated by inhibition of AKT and ERK signaling pathways and modulation of epithelial-mesenchymal transition (EMT).
- F2 was found to reduce P-gp protein levels in HCT8/T cells, contributing to drug resistance reversal.
Conclusions:
- F2 is the first reported FAK-targeted PROTAC molecule with demonstrated efficacy in reversing chemotherapeutic drug resistance.
- The novel PROTAC molecule F2 presents a promising therapeutic strategy for overcoming both cancer growth and multidrug resistance.
- These findings support further research into FAK-targeting PROTACs for potent in vivo anti-cancer applications.
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