title: Development of 1,8-naphthalimides as clathrin inhibitors.
abstract: We reported the first small molecule inhibitors of the interaction between the clathrin N-terminal domain (TD) and endocyctic accessory proteins (i.e., clathrin inhibition1). Initial screening of a ∼17 000 small molecule ChemBioNet library identified 1. Screening of an existing in-house propriety library identified four substituted 1,8-napthalimides as ∼80-120 μM clathrin inhibitors. Focused library development gave 3-sulfo-N-(4-aminobenzyl)-1,8-naphthalimide, potassium salt (18, IC50 ≈ 18 μM). A second library targeting the 4-aminobenzyl moiety was developed, and four analogues displayed comparable activity (26, 27, 28, 34 with IC50 values of 22, 16, 15, and 15 μM respectively) with a further four (24, 25, 32, 33) more active than 18 with IC50 values of 10, 6.9, 12, and 10 μM, respectively. Docking studies rationalized the structure-activity relationship (SAR) with the biological data. 3-Sulfo-N-benzyl-1,8-naphthalimide, potassium salt (25) with an IC50 ≈ 6.9 μM, is the most potent clathrin terminal domain-amphiphysin inhibitor reported to date.
authors.affiliation: Chemistry, Centre for Chemical Biology, The University of Newcastle , University Drive, Callaghan, New South Wales 2308 Australia.
authors.forename: Kylie A
authors.initials: KA
authors.lastname: MacGregor
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Robertson
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Young
authors.forename: Lisa
authors.initials: L
authors.lastname: von Kleist
authors.forename: Wiebke
authors.initials: W
authors.lastname: Stahlschmidt
authors.forename: Ainslie
authors.initials: A
authors.lastname: Whiting
authors.forename: Ngoc
authors.initials: N
authors.lastname: Chau
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Robinson
authors.forename: Volker
authors.initials: V
authors.lastname: Haucke
authors.forename: Adam
authors.initials: A
authors.lastname: McCluskey
mesh_terms: D002966:Clathrin / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D053644:Naphthalimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D002966:Clathrin; D053644:Naphthalimides