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ID: ALA3580578
Journal: Bioorg Med Chem Lett
Title: Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.
Authors: Labadie S, Dragovich PS, Chen J, Fauber BP, Boggs J, Corson LB, Ding CZ, Eigenbrot C, Ge H, Ho Q, Lai KW, Ma S, Malek S, Peterson D, Purkey HE, Robarge K, Salphati L, Sideris S, Ultsch M, VanderPorten E, Wei B, Xu Q, Yen I, Yue Q, Zhang H, Zhang X, Zhou A.
Abstract: Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4–10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.
CiteXplore: 25466195