Discovery of (E)-5-(benzylideneamino)-1H-benzo[d]imidazol-2(3H)-one derivatives as inhibitors for PTK6

Hyun Jae Shim; Hye Ran Yang; Han Ie Kim; Shin-Ae Kang; Kyoung Tai No; Young Hoon Jung; Seung-Taek Lee

doi:10.1016/j.bmcl.2014.08.036

Discovery of (E)-5-(benzylideneamino)-1H-benzo[d]imidazol-2(3H)-one derivatives as inhibitors for PTK6

Bioorg Med Chem Lett. 2014 Oct 1;24(19):4659-4663. doi: 10.1016/j.bmcl.2014.08.036. Epub 2014 Aug 23.

Authors

Hyun Jae Shim¹, Hye Ran Yang², Han Ie Kim¹, Shin-Ae Kang¹, Kyoung Tai No³, Young Hoon Jung⁴, Seung-Taek Lee⁵

Affiliations

¹ Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea.
² School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
³ 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.
⁴ School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: yhjung@skku.edu.
⁵ Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Republic of Korea. Electronic address: stlee@yonsei.ac.kr.

PMID: 25205190
DOI: 10.1016/j.bmcl.2014.08.036

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.

Keywords: Catalytic activity; Inhibitor; PTK6; Structure–activity relationship.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry
Benzimidazoles / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Fibroblasts / cytology
Fibroblasts / drug effects
Foreskin / cytology
Foreskin / drug effects
HEK293 Cells
Humans
Male
Molecular Structure
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / metabolism
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Protein-Tyrosine Kinases / antagonists & inhibitors*
Protein-Tyrosine Kinases / metabolism
Schiff Bases / chemical synthesis
Schiff Bases / chemistry
Schiff Bases / pharmacology*
Structure-Activity Relationship

Substances

5-((2,3-dibromo-5-ethoxy-6-hydroxybenzylidene)amino)-1H-benzo(d)imidazol-2(3H)-one
5-((2,3-dibromo-6-hydroxy-5-methoxybenzylidene)amino)-1H-benzo(d)imidazol-2(3H)-one
Benzimidazoles
Neoplasm Proteins
Protein Kinase Inhibitors
Schiff Bases
Protein-Tyrosine Kinases
PTK6 protein, human