Bisubstrate analogue structure-activity relationships for p300 histone acetyltransferase inhibitors
Department of Biochemistry and Molecular Pharmacology
Medical Subject Headings
Acetyltransferases; Cell Cycle Proteins; Coenzyme A; Enzyme Inhibitors; Histone Acetyltransferases; Lysine; Molecular Structure; Structure-Activity Relationship; Transcription Factors; p300-CBP Transcription Factors
Biochemistry | Enzymes and Coenzymes | Medicinal-Pharmaceutical Chemistry | Therapeutics
p300 and CBP are important histone acetyltransferases (HATs) that regulate gene expression and may be anti-cancer drug targets. Based on a previous lead compound, Lys-CoA, we have used solid phase synthesis to generate a series of 11 new analogues and evaluated these compounds as HAT inhibitors. Increased spacing between the CoA moiety and the lysyl moiety generally decreases inhibitory potency. We have found two substituted derivatives that show about 4-fold increased potency compared to the parent compound Lys-CoA. These structure-activity studies allow for a greater understanding of the optimal requirements for potent inhibition of HAT enzymes and pave the way for a novel class of anti-cancer therapeutics.
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Citation: Bioorg Med Chem. 2004 Jun 15;12(12):3383-90. Link to article on publisher's site
Sagar, Vatsala; Zheng, Weiping; Thompson, Paul R.; and Cole, Philip A., "Bisubstrate analogue structure-activity relationships for p300 histone acetyltransferase inhibitors" (2004). Thompson Lab Publications. 83.