title: Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2.
abstract: Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by hereditary mutations of bile salt export pump (BSEP), such as E297G BSEP, which is a folding-defective mutant that is unable to traffic beyond the endoplasmic reticulum (ER). 4-Phenylbutyric acid (4-PBA) enhances the cell surface expression and transport capacity of E297G BSEP, but has a relatively high dose (1mM or more) is required to show the effect. Here, we show that bile acids possibly act as pharmacological chaperones, promoting the proper folding and trafficking of E297G BSEP. We also describe the discovery and structural development of non-steroidal compounds with potent pharmacological chaperone activity for E297G BSEP.
authors.affiliation: Institute of Molecular and Cellular Biosciencies, The University of Tokyo, 1-1-1 Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Misawa
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Hayashi
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002780:Cholestasis, Intrahepatic / Q000235:genetics; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004721:Endoplasmic Reticulum / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology; D009154:Mutation; D010654:Phenylbutyrates / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490548:Abcb11 protein, rat; D001647:Bile Acids and Salts; D007555:Isoxazoles; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; C412815:GW 4064