title: Synthesis and analysis of potential prodrugs of coenzyme A analogues for the inhibition of the histone acetyltransferase p300.
abstract: Lys-CoA (1) is a selective inhibitor of p300 histone acetyltransferase (HAT) but shows poor pharmacokinetic properties because of its multiply charged phosphates. In an effort to overcome this limitation, truncated derivatives of 1 were designed, synthesized and tested as p300HAT inhibitors as well as substrates for the CoA biosynthetic bifunctional enzyme phosphopantetheine adenylyltransferase-dephospho-CoA kinase (PPAT/DPCK). Lys-pantetheine (3) and Lys-phosphopantetheine (2) showed no detectable p300HAT inhibition whereas 3'-dephospho-Lys-CoA (5) was a modest p300 inhibitor with IC(50) of 1.6 microM (compared to IC(50) of approximately 50 nM for 1 blocking p300). Compound 2 was shown to be an efficient substrate for PPAT whereas 5 was a very poor DPCK substrate. Further analysis with 3'-dephospho-Me-SCoA (7) indicated that DPCK shows relatively narrow capacity to accept substrates with sulfur substitution. While these results suggest that truncated derivatives of 1 will be of limited value as lead agents for p300 blockade in vivo, they augur well for prodrug versions of CoA analogues that do not require 3'-phosphate substitution for efficient binding to their targets, such as the GCN-5 related N-acetyltransferases.
authors.affiliation: Department of Pharmacology and Molecular Sciences, Johns Hopkins University, School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
authors.forename: Marek
authors.initials: M
authors.lastname: Cebrat
authors.forename: Cheol M
authors.initials: CM
authors.lastname: Kim
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.forename: Matthew
authors.initials: M
authors.lastname: Daugherty
authors.forename: Philip A
authors.initials: PA
authors.lastname: Cole
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003065:Coenzyme A / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051548:Histone Acetyltransferases; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D011355:Prodrugs; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D003065:Coenzyme A