Targeted Degradation of Lin28B Using Pre-let-7-PROTACs for Hepatocellular Carcinoma Therapy

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Hepatocellular carcinoma (HCC) presents significant challenges, including high recurrence, mortality, and drug resistance.
• Lin28B, an RNA-binding protein overexpressed in HCC, drives tumor progression and inhibits tumor-suppressive let-7 miRNAs.
• Lin28B is considered an undruggable target due to the absence of conventional small-molecule binding pockets.

Purpose of the Study:

• To develop novel targeted therapies for HCC by targeting the undruggable Lin28B protein.
• To investigate the therapeutic potential of pre-let-7-PROTACs for HCC treatment.
• To evaluate the efficacy of pre-let-7-PROTACs in combination with sorafenib.

Main Methods:

• Construction of pre-let-7-PROTACs by conjugating pre-let-7 miRNAs with E3 ligase ligands.
• Assessment of Lin28B degradation and restoration of mature let-7 expression.
• Evaluation of HCC cell proliferation, migration, apoptosis, and chemosensitivity.
• Testing pre-let-7-PROTACs in a Huh-7 xenograft tumor model, alone and with sorafenib.

Main Results:

• Pre-let-7-PROTACs efficiently and specifically degraded Lin28B and restored endogenous mature let-7 levels.
• Treatment with pre-let-7-PROTACs suppressed HCC cell proliferation and migration, promoted apoptosis, and enhanced chemosensitivity.
• In vivo studies demonstrated synergistic antitumor effects of pre-let-7-PROTACs combined with sorafenib in a HCC xenograft model.
• Pre-let-7-PROTACs were shown to reduce tumor stemness by degrading Lin28B.

Conclusions:

• Pre-let-7-PROTACs represent a promising therapeutic strategy for targeting Lin28B in HCC.
• This approach offers a novel way to overcome the 'undruggable' nature of Lin28B.
• The combination of pre-let-7-PROTACs and sorafenib shows significant potential for HCC treatment.