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

Arsenic
trioxide (ATO) targets PML/RARα and leads to miraculous
success in treating acute promyelocytic leukemia. Notably, ATO also
targets p53, the most frequently mutated protein in cancers, through
a similar binding mechanism. However, p53-targeting ATO trials are
challenging due to the poor cellular uptake and cancer selectivity
of ATO. Here, we analyzed the structure–activity relationship
of arsenicals and rationally developed a novel arsenical (designated
AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake
through a thiol-mediated pathway (maximally 127-fold higher than ATO),
thereby potently targeting PML/RARα and mutant p53. Among the
55 tested cell lines, AcGlcAs preferentially killed cancer lines rather
than normal lines. In preclinical studies, AcGlcAs significantly extended
the survival of mice bearing a xenograft tumor with p53 mutation while
showing high plasma stability and oral bioavailability. Thus, AcGlcAs
is a potential clinical candidate for precisely treating numerous
p53-mutated cancers.