title: Synthesis and structure-activity relationship of (1-halo-2-naphthyl) carbamate-based inhibitors of KIAA1363 (NCEH1/AADACL1).
abstract: KIAA1363 is a serine hydrolase whose activity has been shown to be positively associated with tumor cell invasiveness. Thus, inhibitors of KIAA1363 represent a novel targeted therapy approach towards cancer. AX11890 ((1-bromo-2-naphthyl) N,N-dimethylcarbamate) was identified as a KIAA1363 inhibitor with an IC(50) value of 1.2 μM and was shown using ESI-MS to carbamylate the catalytic residue Ser(191). SAR studies explored both substitution of the 1-bromo group and derivatization of the 6-position. Activity-based protein profiling demonstrated AX13057 inhibited tumor-localized KIAA1363 in SK-OV-3 xenograft-bearing mice.
authors.affiliation: ActivX Biosciences, Inc., 11025 N. Torrey Pines Road, La Jolla, CA 92037, USA. kevins@activx.com
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Shreder
authors.forename: Emme C K
authors.initials: EC
authors.lastname: Lin
authors.forename: Jiangyue
authors.initials: J
authors.lastname: Wu
authors.forename: Julia
authors.initials: J
authors.lastname: Cajica
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Amantea
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Eric
authors.initials: E
authors.lastname: Okerberg
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Brown
authors.forename: Lan M
authors.initials: LM
authors.lastname: Pham
authors.forename: De Michael
authors.initials: de M
authors.lastname: Chung
authors.forename: Allister S
authors.initials: AS
authors.lastname: Fraser
authors.forename: Ethel
authors.initials: E
authors.lastname: McGee
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Rosenblum
authors.forename: John W
authors.initials: JW
authors.lastname: Kozarich
mesh_terms: D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002265:Carboxylic Ester Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism; D002787:Sterol Esterase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D002219:Carbamates; D004791:Enzyme Inhibitors; D002265:Carboxylic Ester Hydrolases; C514712:Nceh1 protein, mouse; C515677:NCEH1 protein, human; D002787:Sterol Esterase