%0 Journal Article
%T Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors.
%A Burkett DJ
%A Wyatt BN
%A Mews M
%A Bautista A
%A Engel R
%A Dockendorff C
%A Donaldson WA
%A St Maurice M
%J Bioorg Med Chem
%V 27
%N 18
%D 09 2019 15
%M 31351848
%F 3.461
%R 10.1016/j.bmc.2019.07.027
%X Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3'-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase.