Cebrat Marek, Kim Cheol M, Thompson Paul R, Daugherty Matthew, Cole Philip A
Department of Pharmacology and Molecular Sciences, Johns Hopkins University, School of Medicine, 725 N. Wolfe Street, Baltimore, MD 21205, USA
Bioorg Med Chem. 2003 Jul 31;11(15):3307-13. doi: 10.1016/s0968-0896(03)00265-7.
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.
赖氨酸辅酶A（1）是p300组蛋白乙酰转移酶（HAT）的选择性抑制剂，但由于其多个带电荷的磷酸基团，表现出较差的药代动力学性质。为了克服这一限制，设计、合成并测试了1的截短衍生物作为p300HAT抑制剂以及辅酶A生物合成双功能酶磷酸泛酰巯基乙胺腺苷酰转移酶-脱磷酸辅酶A激酶（PPAT/DPCK）的底物。赖氨酸泛酰巯基乙胺（3）和赖氨酸磷酸泛酰巯基乙胺（2）未显示出可检测到的p300HAT抑制作用，而3'-脱磷酸赖氨酸辅酶A（5）是一种适度的p300抑制剂，IC50为1.6微摩尔（相比之下，1阻断p300的IC50约为50纳摩尔）。化合物2被证明是PPAT的有效底物，而5是非常差的DPCK底物。用3'-脱磷酸甲基硫代辅酶A（7）进行的进一步分析表明，DPCK接受硫取代底物的能力相对较窄。虽然这些结果表明，1的截短衍生物作为体内p300阻断的先导药物价值有限，但它们对于不需要3'-磷酸取代就能有效结合其靶点的辅酶A类似物的前药版本（如与GCN-5相关的N-乙酰转移酶）来说是个好兆头。
