Design of Murine Double Minute 2 Proteolysis Targeting Chimera Degraders with a Built-In Tumor-Targeting Ability

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Proteolysis targeting chimeras (PROTACs) are heterobifunctional molecules designed for targeted protein degradation.
• Murine double minute 2 (MDM2) is an oncogenic protein and a target for cancer therapy.
• Existing PROTACs lack tumor-targeting capabilities, limiting their therapeutic application.

Purpose of the Study:

• To develop tumor-targeting PROTACs for the degradation of oncogenic MDM2.
• To evaluate the efficacy and safety of novel AS1411-based MDM2 degraders.

Main Methods:

• Conjugation of the tumor-targeting aptamer AS1411 with a von Hippel-Lindau (VHL) ligase recruiter (VH032) to create AS1411-VH032.
• Development of an AS1411-based homo-PROTAC (homoAS1411) for MDM2 self-degradation.
• Assessment of tumor-selective MDM2 degradation, tumor shrinkage, and toxicity in preclinical models.

Main Results:

• AS1411-VH032 demonstrated tumor-selective degradation of MDM2, leading to significant tumor shrinkage.
• HomoAS1411 induced tumor-specific MDM2 degradation, effectively preventing tumor progression.
• Both novel PROTACs exhibited a favorable safety profile with no detectable toxicity.

Conclusions:

• AS1411-VH032 and homoAS1411 represent promising therapeutic strategies for targeting MDM2 in cancer.
• The built-in tumor-targeting ability of these PROTACs enhances antitumor efficacy while maintaining safety.
• These findings pave the way for developing targeted protein degradation therapies with improved therapeutic windows.