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Targeted degradation of anaplastic lymphoma kinase by gold nanoparticle-based multi-headed proteolysis targeting
Yingming Wang1, Lingfei Han1, Fulei Liu2
1Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, Jiangsu 210009, China.
Abstract:
Anaplastic lymphoma kinase (ALK) is a major target in treating non-small-cell lung cancer, and several ALK inhibitors have been developed to antagonize its kinase activity. However, patients treated with inhibitors ultimately develop drug resistance. Therefore, therapies with new mechanisms of action are needed. Proteolysis targeting chimeras (PROTACs) are molecules that comprise a ligand for binding a protein of interest (POI), a connecting linker and a ligand for recruiting E3 ligase, and cause degradation of the target POI. Here, the first multi-headed PROTAC, as a proof of concept, is developed as a gold nanoparticle (GNP)-based drug delivery system for delivering PROTACs to target ALK. Pegylated GNPs loaded with both ceritinib and pomalidomide molecules, termed Cer/Pom-PEG@GNPs, showed good stability in several media. The GNP conjugates potently decreased the levels of ALK fusion proteins in a dose- and time-dependent manner, and specifically inhibited the proliferation of NCI-H2228 cells. In comparison with small molecule PROTACs, the new multi-headed PROTAC promoted the formation of coacervates of POIs/multi-headed PROTAC/E3 ubiquitin ligases, and POI and E3 ubiquitin ligase interacted through multidirectional ligands and a flexible linker, thereby avoiding the need for complicated structure optimization of PROTACs. In conclusion, Cer/Pom-PEG@GNPs can degrade intracellular ALK fusion proteins with minor off-target toxicity and can be applied in patients resistant to ALK inhibitors. As a nano-based drug carrier, Cer/Pom-PEG@GNPs have the potential to enable prolonged circulation and specifically distribute drugs to tumor regions in vivo; thus, further investigation is warranted.
Insights
New gold nanoparticle-based PROTACs effectively degrade anaplastic lymphoma kinase (ALK) fusion proteins, offering a promising therapy for non-small-cell lung cancer patients resistant to ALK inhibitors.
Area of Science:
- Oncology
- Nanotechnology
- Drug Discovery
Background:
- Anaplastic lymphoma kinase (ALK) is a key target in non-small-cell lung cancer (NSCLC).
- Drug resistance to existing ALK inhibitors necessitates novel therapeutic strategies.
- Proteolysis targeting chimeras (PROTACs) offer a new mechanism for targeted protein degradation.
Purpose of the Study:
- To develop and evaluate a novel multi-headed PROTAC delivery system using gold nanoparticles (GNPs) to target ALK.
- To assess the efficacy and stability of the developed PROTAC-loaded GNPs in degrading ALK fusion proteins.
Main Methods:
- Conjugation of ceritinib and pomalidomide onto pegylated gold nanoparticles (Cer/Pom-PEG@GNPs).
- Assessment of nanoparticle stability in various media.
- Evaluation of ALK fusion protein degradation and cell proliferation inhibition in NCI-H2228 cells.
- Comparison of multi-headed PROTACs with small molecule PROTACs regarding protein-target complex formation.
Main Results:
- Cer/Pom-PEG@GNPs demonstrated good stability.
- The conjugates effectively reduced ALK fusion protein levels in a dose- and time-dependent manner.
- Specific inhibition of NCI-H2228 cell proliferation was observed.
- Multi-headed PROTACs promoted coacervate formation, facilitating protein degradation.
Conclusions:
- Cer/Pom-PEG@GNPs represent a novel multi-headed PROTAC system for degrading intracellular ALK fusion proteins.
- This approach shows potential for treating ALK inhibitor-resistant NSCLC with minimal off-target toxicity.
- The nano-based drug carrier system may offer advantages in drug circulation and tumor-specific distribution.
