Evaluation of α-hydroxycinnamic acids as pyruvate carboxylase inhibitors.
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.
['Burkett|Daniel J|DJ|', 'Wyatt|Brittney N|BN|', 'Mews|Mallory|M|', 'Bautista|Anson|A|', 'Engel|Ryan|R|', 'Dockendorff|Chris|C|', 'Donaldson|William A|WA|', 'St Maurice|Martin|M|']
D003373:Coumaric Acids D015195:Drug Design D006801:Humans D011766:Pyruvate Carboxylase
α-Hydroxycinnamic acids Pyruvate carboxylase α-Keto acids Carboxyltransferase