Abstract:
Background: 1,4-Naphthoquinone analogs, such as plumbagin, are toxic compounds due to their redox cycling and thiol-reactive properties. Results: The p300 inhibitor PTK1, a plumbagin derivative with greatly reduced toxicity, was synthesized and characterized. Conclusion: PTK1 is a reversible, non-competitive inhibitor of p300 KAT activity with reduced toxicity. Significance: These studies provide insight into naphthoquinone-mediated KAT inhibition and describe the synthesis of a therapeutically important, non-toxic inhibitor. Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4-naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor.
