title: Discovery of (E)-5-(benzylideneamino)-1H-benzo[d]imidazol-2(3H)-one derivatives as inhibitors for PTK6.
abstract: A lead compound 1, which inhibits the catalytic activity of PTK6, was selected from a chemical library. Derivatives of compound 1 were synthesized and analyzed for inhibitory activity against PTK6 in vitro and at the cellular level. Selected compounds were analyzed for cytotoxicity in human foreskin fibroblasts using MTT assays and for selectivity towards PTK members in HEK 293 cells. Compounds 20 (in vitro IC50=0.12μM) and 21 (in vitro IC50=0.52μM) showed little cytotoxicity, excellent inhibition of PTK6 in vitro and at the cellular level, and selectivity for PTK6. Compounds 20 and 21 inhibited phosphorylation of specific PTK6 substrates in HEK293 cells. Thus, we have identified novel PTK6 inhibitors that may be used as treatments for PTK6-positive carcinomas, including breast cancer.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Hyun Jae
authors.initials: HJ
authors.lastname: Shim
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Hye Ran
authors.initials: HR
authors.lastname: Yang
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Han Ie
authors.initials: HI
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
authors.forename: Shin-Ae
authors.initials: SA
authors.lastname: Kang
authors.affiliation: Bioinformatics and Molecular Design Research Center, 120-749 Seoul, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Kyoung Tai
authors.initials: KT
authors.lastname: No
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yhjung@skku.edu.
authors.forename: Young Hoon
authors.initials: YH
authors.lastname: Jung
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Electronic address: stlee@yonsei.ac.kr.
authors.forename: Seung-Taek
authors.initials: ST
authors.lastname: Lee
mesh_terms: D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D052816:Foreskin / Q000166:cytology / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D015394:Molecular Structure; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012545:Schiff Bases / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: C000596296:5-((2,3-dibromo-5-ethoxy-6-hydroxybenzylidene)amino)-1H-benzo(d)imidazol-2(3H)-one; C000596295:5-((2,3-dibromo-6-hydroxy-5-methoxybenzylidene)amino)-1H-benzo(d)imidazol-2(3H)-one; D001562:Benzimidazoles; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D012545:Schiff Bases; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human
keywords: Catalytic activity; Inhibitor; PTK6; Structure–activity relationship