Synthesis and structure-activity relationship of (1-halo-2-naphthyl) carbamate-based inhibitors of KIAA1363 (NCEH1/AADACL1).

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. Copyright © 2012. Published by Elsevier Ltd.

Citation

Kevin R Shreder, Emme C K Lin, Jiangyue Wu, Julia Cajica, Christopher M Amantea, Yi Hu, Eric Okerberg, Heidi E Brown, Lan M Pham, De Michael Chung, Allister S Fraser, Ethel McGee, Jonathan S Rosenblum, John W Kozarich. Synthesis and structure-activity relationship of (1-halo-2-naphthyl) carbamate-based inhibitors of KIAA1363 (NCEH1/AADACL1). Bioorganic & medicinal chemistry letters. 2012 Sep 1;22(17):5748-51

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PMID: 22877630

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