Naphthoquinone-mediated Inhibition of Lysine Acetyltransferase KAT3B/p300, Basis for Non-toxic Inhibitor Synthesis

Abstract

Background: 1,4-Naphthoquinone analogs, such as plumbagin, are toxic compounds due to their redox cycling and thiolreactive 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.

Posttranslational Regulation of Human DNA Polymerase ι

“…It is apparent that the effects of menadione, juglone, 1,4-naphthoquinone, and plumbagin cannot be simply attributed to oxidative DNA damage or mitochondrial dysfunction. However, naphthoquinones are also known to inhibit the activity of the lysine acetyltransferase KAT3B/p300 ( 58 , 59 ). We therefore considered the possibility that the inhibition of ubiquitin acetylation may promote the polyubiquitination of polι.…”

“…However, in addition to the induction of reactive oxygen species, the naphthoquinones are also known to exert a wide range of cellular effects leading to stress signaling, antiangiogenesis, and thiolate arylation of proteins and amines ( 64 – 66 ). One property of interest is their ability to inhibit the lysine acetyltransferase (KAT) p300 ( 58 , 59 ). All of the naphthoquinones (1,4-naphthoquinone, menadione, juglone, and plumbagin) that induced polι polyubiquitination have previously been reported to inhibit the KAT activity of p300 ( 59 ).…”

“…One property of interest is their ability to inhibit the lysine acetyltransferase (KAT) p300 ( 58 , 59 ). All of the naphthoquinones (1,4-naphthoquinone, menadione, juglone, and plumbagin) that induced polι polyubiquitination have previously been reported to inhibit the KAT activity of p300 ( 59 ). It is unknown whether DMNQ (which did not cause polι polyubiquitination) can inhibit the KAT activity of p300.…”

Emerging Epigenetic Therapies

“…This molecule retains all the other properties of plumbagin but they generate negligible ROS via redox cycling [161]. By exploiting the chemical structure and functional properties of this 1,4-naphthoquinone class of molecules, recently a nontoxic yet equally potent p300 KAT inhibitor, PTK1 was reported.…”

The Wild-type and Gain-of-function Mutant p53 Enhance p300 Autoacetylation through Conformational Switching

“…p53 interacts with p300 in its tetrameric conformation, through its bipartite transactivation domain AD1 and AD2, while p300 interacts through several domains namely, TAZ1, KIX, TAZ2 and IBiD (26,27). Intriguingly, numerous factors such as E1A, DDX24, WTX, MYBB1A, Skp2, can regulate p53 tumor suppressive functions in vivo by dictating its association with p300, thereby proving that the p300-p53 axis is an important cell fate determinant in stress responses (18,(28)(29)(30)(31)(32). The p53 gene acquires several mutations which abolish its tumor suppressive functions and confer oncogenic gain-of-function properties which contribute to tumorigenesis.…”