title: Identification of KPNB1 as a Cellular Target of Aminothiazole Derivatives with Anticancer Activity.
abstract: We found that aminothiazole derivative (E)-N-(5-benzylthiazol-2-yl)-3-(furan-2-yl)acrylamide (1) has strong anticancer activity, and undertook proteomics approaches to identify the target protein of compound 1, importin β1 (KPNB1). A competitive binding assay using fluorescein-labeled 1 showed that 1 has strong binding affinity for KPNB1 (Kd : ∼20 nm). Furthermore, through western blotting assays for KPNB1, KPNA2, EGFR, ErbB2, and STAT3, we confirmed that 1 has inhibitory effects on the importin pathway. KPBN1 appears to be overexpressed in several cancer cells, and siRNA-induced inhibition of KPNB1 shows significant inhibition of cancer cell proliferation, while leaving non-cancerous cells unaffected. Therefore, compound 1 is a promising new lead for the development of KPNB1-targeted anticancer agents. Fluorescein-labeled 1 could be a useful quantitative probe for the development of novel KPNB1 inhibitors.
authors.affiliation: Department, Catholic University of Daegu School of Medicine, 3056-6 Daemyeong 4-dong, Nam-gu, Daegu, 705-718, Republic of Korea.
authors.forename: Yong-Hak
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Chung-Ang University, 221 Heakseok-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea.
authors.forename: Siyoung
authors.initials: S
authors.lastname: Ha
authors.affiliation: Department of Chemistry, Chung-Ang University, 221 Heakseok-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea.
authors.forename: Jungwon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Chemistry, Chung-Ang University, 221 Heakseok-dong, Dongjak-gu, Seoul, 156-756, Republic of Korea. swham@cau.ac.kr.
authors.forename: Seung Wook
authors.initials: SW
authors.lastname: Ham
mesh_terms: D015086:2,6-Dichloroindophenol / Q000737:chemistry; D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D052160:Benzothiazoles / Q000737:chemistry / Q000494:pharmacology*; D005452:Fluoresceins / Q000737:chemistry; D005456:Fluorescent Dyes / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D062105:Molecular Docking Simulation; D010084:Oxidation-Reduction; D011808:Quinone Reductases / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D028961:beta Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000178:Acrylamides; D000970:Antineoplastic Agents; D052160:Benzothiazoles; D005452:Fluoresceins; D005456:Fluorescent Dyes; C424166:KPNB1 protein, human; C000622555:N-(5-benzylthiazol-2-yl)-3-(furan-2-yl)acrylamide; D028961:beta Karyopherins; D015086:2,6-Dichloroindophenol; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases
keywords: KPNB1; LC-MS/MS; anticancer agents; competitive binding; proteomics