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Bioorg Med Chem Lett. 2016 Apr 1;26(7):1720-5. doi: 10.1016/j.bmcl.2016.02.052. Epub 2016 Feb 20.

Novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety against anaplastic lymphoma kinase (ALK): Synthesis, in vitro, ex vivo, and in vivo efficacy studies.

Author information

1
College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
2
Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
3
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea.
4
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
5
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: hyngrk@krict.re.kr.
6
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea. Electronic address: jyhwang@krict.re.kr.

Abstract

A series of novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety were synthesized and evaluated for their anti-anaplastic lymphoma kinase (ALK) activities using enzymatic and cell-based assays. Among the compounds synthesized, compound 17b showed promising pharmacological results in in vitro, ex vivo, and pharmacokinetic studies. An in vivo efficacy study with compound 17b demonstrated highly potent inhibitory activity in H3122 tumor xenograft model mice. A series of kinase assays showed that compound 17b inhibited various kinases including FAK, ACK1, FGFR, RSK1, IGF-1R, among others, thus demonstrating its potential for synergistic anti-tumor activity and development as a multi-targeted non-small cell lung cancer (NSCLC) therapy.

KEYWORDS:

2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Tetrahydronaphthalenyl

PMID:
26923695
DOI:
10.1016/j.bmcl.2016.02.052
[Indexed for MEDLINE]

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