title: A structure-activity relationship study of small-molecule inhibitors of GLI1-mediated transcription.
abstract: We have previously reported ketoprofen amide compounds as inhibitors of GLI1-mediated transcription, an essential down-stream element of the Hedgehog (Hh) pathway. These compounds inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1. Here we have designed new derivatives of these compounds aiming to explore the structure-activation relationship (SAR). By replacing the ketone carbonyl group of the ketoprofen moiety with an ether, amide, sulfonamide, or sulfone, we found several new compounds that are equipotent to the ketoprofen amide compounds. Among them, sulfone 30 inhibited Gli-luciferase reporter in C3H10T1/2 cells that were exogenously transfected with GLI1 and in Rh30 cells that endogenously overexpress GLI1.
authors.affiliation: Medicinal Chemistry Center, Departments of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Actis
authors.forename: Michele C
authors.initials: MC
authors.lastname: Connelly
authors.forename: Anand
authors.initials: A
authors.lastname: Mayasundari
authors.forename: Chandanamali
authors.initials: C
authors.lastname: Punchihewa
authors.forename: Naoaki
authors.initials: N
authors.lastname: Fujii
mesh_terms: D001704:Biopolymers / Q000737:chemistry* / Q000494:pharmacology; D002478:Cells, Cultured; D015195:Drug Design; D015394:Molecular Structure; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000737:chemistry; D014158:Transcription, Genetic; D000071676:Zinc Finger Protein GLI1
chemical_list: D001704:Biopolymers; C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1