AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Arsenic trioxide (ATO) is effective against acute promyelocytic leukemia by targeting PML/RARα.
• ATO also interacts with p53, a frequently mutated protein in various cancers, but faces challenges in cellular uptake and cancer selectivity.
• Targeting mutant p53 holds significant therapeutic potential for a broad range of cancers.

Purpose of the Study:

• To develop a novel arsenical compound with enhanced cellular uptake and improved targeting of PML/RARα and mutant p53.
• To evaluate the cancer cell selectivity and preclinical efficacy of the novel arsenical.

Main Methods:

• Structure-activity relationship analysis of arsenicals.
• Rational design and synthesis of a novel arsenical (AcGlcAs) by conjugating arsenic to sulfur and tetraacetyl-β-d-thioglucose.
• Assessment of cellular uptake via thiol-mediated pathways.
• In vitro evaluation of targeting PML/RARα and mutant p53 across 55 cancer cell lines.
• Preclinical studies in mice with p53-mutated xenograft tumors.

Main Results:

• AcGlcAs demonstrated significantly higher cellular uptake (up to 127-fold) compared to ATO.
• AcGlcAs potently targeted both PML/RARα and mutant p53.
• The compound exhibited preferential cytotoxicity towards cancer cell lines over normal cell lines.
• AcGlcAs significantly improved survival in mice with p53-mutated xenograft tumors.
• AcGlcAs showed good plasma stability and oral bioavailability.

Conclusions:

• AcGlcAs represents a promising new arsenical derivative with enhanced cellular uptake and potent dual targeting of PML/RARα and mutant p53.
• Its selective cancer cell killing and favorable preclinical profile suggest AcGlcAs is a potential clinical candidate for treating p53-mutated cancers.