New potent bisubstrate inhibitors of histone acetyltransferase p300: design, synthesis and biological evaluation.
Bisubstrate-type compound Lys-CoA has been shown to inhibit the p300 histone acetyl transferase activity efficiently and may constitute a lead compound for a novel class of anticancer therapeutics. Based on this strategy, we synthesized a series of CoA derivatives and evaluated these molecules for their activity as p300 histone acetyltransferases inhibitor. The best activity was obtained with compound 3 bearing a C-5 spacing linker that connects the CoA moiety to a tert-butyloxycarbonyl (Boc) group. Based on docking simulations, this inhibitor exhibits favorable interactions with two binding areas, namely pockets P1 and P2, within the active site.
CNRS, Laboratoire de Synthèse et Physico-Chimie de Molécules d'Intérêt Biologique, SPCMIB, UMR-5068, 118 Route de Narbonne, Toulouse Cedex 9, France.
Franciane Ho A
FH
Kwie
Martine
M
Briet
David
D
Soupaya
Pascal
P
Hoffmann
Marie
M
Maturano
Frédéric
F
Rodriguez
Casimir
C
Blonski
Christian
C
Lherbet
Cécile
C
Baudoin-Dehoux
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D003065:Coenzyme A / Q000138:chemical synthesis* / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D015203:Reproducibility of Results; D012107:Research Design
D000577:Amides; D004791:Enzyme Inhibitors; D051548:Histone Acetyltransferases; D003065:Coenzyme A