<br/>Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia that is characterized by a translocation of chromosomes 15 and 17, t(15;17), that results in formation of the oncogenic PML-RARα fusion protein. Arsenic trioxide is an FDA-approved treatment for APL, with long-term survival rates reaching 90%. Arsenic trioxide is hydrolyzed in the body to arsenous acid and further metabolized to methylarsonic acid and dimethylarsinic acid, which work synergistically to induce apoptosis and cell differentiation. The ability of arsenic trioxide to induce cell differentiation appears to be related to the capacity of its biotransformation products to crosslink cysteine thiolates groups. Despite its clinical success, the application of arsenic trioxide is limited by off-target toxicity and resistance to treatment. We are investigating whether molecules that maintain the characteristic thiol-crosslinking chemistry of arsenic trioxide but feature a greater degree of tunability can overcome the current limitations of arsenic-based anti-APL therapy. We are specifically targeting arylarsonic acids, which have the same thiol-facing reactivity but have distinct, and tunable, physiochemical properties when compared to arsenic trioxide. A series of arylarsonic acids have been prepared and characterized and we have studied the impact of variation of aryl ring substituents on biologically relevant parameters such as lipophilicity and rate of chemical reduction. We assessed the correlations between these physiochemical properties and biological activity using in vitro cell uptake and cell differentiation assays. These results form the basis for a more systematic investigation of the role that organoarsenic species can play in the treatment of leukemia.

Arylarsonic acids as an alternative to arsenic trioxide for the treatment of acute promyelocytic leukemia

ACS Spring 2022

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