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

Research paper by Kevin R KR Shreder, Emme C K EC Lin, Jiangyue J Wu, Julia J Cajica, Christopher M CM Amantea, Yi Y Hu, Eric E Okerberg, Heidi E HE Brown, Lan M LM Pham, De Michael de M Chung, Allister S AS Fraser, Ethel E McGee, Jonathan S JS Rosenblum, John W JW Kozarich

Indexed on: 11 Aug '12Published on: 11 Aug '12Published in: Bioorganic & Medicinal Chemistry Letters


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.