title: Development of a triazole class of highly potent Porcn inhibitors.
abstract: The acyltransferase Porcupine (Porcn) is essential for the secretion of Wnt proteins which contribute to embryonic development, tissue regeneration, and tumorigenesis. We have previously discovered four molecular scaffolds harboring Porcn-inhibitory activity. Comparison of their structures led to the identification of a general scaffold that can be readily assembled by modular synthesis. We report herein the development of a triazole version of this new class of Porcn inhibitors. This study yielded IWP-O1, a Porcn inhibitor with an EC50value of 80pM in a cultured cell reporter assay of Wnt signaling. Additionally, IWP-O1 has significantly improved metabolic stability over our previously reported Porcn inhibitors.
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: You
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chengwei
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nageswari
authors.initials: N
authors.lastname: Yarravarapu
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Morlock
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lishu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Lum
authors.affiliation: Department of Biochemistry, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: chuo.chen@utsouthwestern.edu.
authors.forename: Chuo
authors.initials: C
authors.lastname: Chen
mesh_terms: D000217:Acyltransferases; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D008565:Membrane Proteins; D014230:Triazoles; D000217:Acyltransferases; C491188:PORCN protein, human
keywords: Biaryl amide; Porcupine; Triaryl; Triazole; Wnt signaling