title: Selective Inhibition of Collagen Prolyl 4-Hydroxylase in Human Cells.
abstract: Collagen is the most abundant protein in animals. Its overproduction is associated with fibrosis and cancer metastasis. The stability of collagen relies on post-translational modifications, the most prevalent being the hydroxylation of collagen strands by collagen prolyl 4-hydroxylases (CP4Hs). Catalysis by CP4Hs enlists an iron cofactor to convert proline residues to 4-hydroxyproline residues, which are essential for the conformational stability of mature collagen. Ethyl 3,4-dihydroxybenzoate (EDHB) is commonly used as a "P4H" inhibitor in cells, but suffers from low potency, poor selectivity, and off-target effects that cause iron deficiency. Dicarboxylates of 2,2'-bipyridine are among the most potent known CP4H inhibitors but suffer from a high affinity for free iron. A screen of biheteroaryl compounds revealed that replacing one pyridyl group with a thiazole moiety retains potency and enhances selectivity. A diester of 2-(5-carboxythiazol-2-yl)pyridine-5-carboxylic acid is bioavailable to human cells and inhibits collagen biosynthesis at concentrations that neither cause general toxicity nor disrupt iron homeostasis. These data anoint a potent and selective probe for CP4H and a potential lead for the development of a new class of antifibrotic and antimetastatic agents.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.
authors.forename: James D
authors.initials: JD
authors.lastname: Vasta
authors.affiliation: Graduate Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison , 1300 University Avenue, Madison, Wisconsin 53706, United States.
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Andersen
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison , 1415 Linden Drive, Madison, Wisconsin 53706, United States.
authors.forename: Kathryn M
authors.initials: KM
authors.lastname: Deck
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison , 1415 Linden Drive, Madison, Wisconsin 53706, United States.
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Nizzi
authors.affiliation: Department of Nutritional Sciences, University of Wisconsin-Madison , 1415 Linden Drive, Madison, Wisconsin 53706, United States.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Eisenstein
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison , 433 Babcock Drive, Madison, Wisconsin 53706, United States.|Department of Chemistry, University of Wisconsin-Madison , 1101 University Avenue, Madison, Wisconsin 53706, United States.
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Raines
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D011393:Procollagen-Proline Dioxygenase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D013844:Thiazoles; D011393:Procollagen-Proline Dioxygenase