An engineered DNA aptamer-based PROTAC for precise therapy of p53-R175H hotspot mutant-driven cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Mutant p53 proteins, frequently overexpressed in cancers, possess oncogenic gain-of-function activities.
• The lack of a druggable active site in mutant p53 hinders small molecule-based cancer therapies.
• Targeting mutant p53 is a promising strategy for developing novel cancer treatments.

Purpose of the Study:

• To develop a selective proteolysis-targeting chimera (PROTAC) targeting the common p53-R175H mutant.
• To engineer a high-affinity DNA aptamer for p53-R175H using a novel computational approach.
• To evaluate the therapeutic potential of the developed PROTAC in preclinical cancer models.

Main Methods:

• A novel iterative molecular docking-guided post-SELEX approach was employed to engineer a DNA aptamer.
• The aptamer was utilized as a binder component in the rational design of a PROTAC molecule (dp53m).
• The efficacy and selectivity of dp53m were assessed in vitro and in vivo using cancer cells harboring p53-R175H mutations.

Main Results:

• A selective p53-R175H degrader, dp53m, was successfully developed, targeting the mutant protein for ubiquitin-proteasome degradation.
• dp53m demonstrated significant antitumor activity in p53-R175H-driven cancer cells without observable toxicity.
• Co-administration of dp53m with cisplatin synergistically enhanced the sensitivity of cancer cells to chemotherapy.

Conclusions:

• The developed PROTAC, dp53m, offers a promising therapeutic strategy for cancers driven by p53-R175H mutations.
• Targeted degradation of mutant p53 via PROTACs represents a viable approach to overcome therapeutic resistance.
• dp53m shows potential for combination therapy to improve treatment outcomes in specific cancer types.