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.

Hyun Jae Shim ¹, Hye Ran Yang ², Han Ie Kim ¹, Shin-Ae Kang ¹, Kyoung Tai No ³, Young Hoon Jung ⁴, Seung-Taek Lee ⁵

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.

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