Cebrat, MarekKim, Cheol M.Thompson, Paul RDaugherty, MatthewCole, Philip A.2022-08-232022-08-232003-07-312015-06-05Bioorg Med Chem. 2003 Jul 31;11(15):3307-13. doi:10.1016/S0968-0896(03)00265-70968-0896 (Linking)10.1016/S0968-0896(03)00265-7https://hdl.handle.net/20.500.14038/50081<p>At the time of publication, Paul Thompson was not yet affiliated with UMass Medical School.</p>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.en-USAcetyltransferasesCoenzyme AHistone AcetyltransferasesHumansProdrugsBiochemistryEnzymes and CoenzymesMedicinal-Pharmaceutical ChemistryTherapeuticsJournal Articlehttps://escholarship.umassmed.edu/thompson/867185898thompson/86