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

Dawn Song; Minji Lee; Chi Hoon Park; Sunjoo Ahn; Chang Soo Yun; Chong Ock Lee; Hyoung Rae Kim; Jong Yeon Hwang

doi:10.1016/j.bmcl.2016.02.052

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

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

Authors

Dawn Song¹, Minji Lee², Chi Hoon Park³, Sunjoo Ahn³, Chang Soo Yun³, Chong Ock Lee⁴, Hyoung Rae Kim⁵, Jong Yeon Hwang⁶

Affiliations

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.

PMID: 26923695
DOI: 10.1016/j.bmcl.2016.02.052

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.

Publication types

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

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / therapeutic use*
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Cell Line, Tumor
Humans
Lung / drug effects
Lung / enzymology
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Male
Mice
Mice, SCID
Naphthalenes / chemistry
Naphthalenes / pharmacokinetics
Naphthalenes / therapeutic use
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / chemistry*
Pyrimidines / pharmacokinetics
Pyrimidines / therapeutic use*
Rats
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*
Receptor Protein-Tyrosine Kinases / metabolism

Substances

Antineoplastic Agents
Naphthalenes
Protein Kinase Inhibitors
Pyrimidines
2,4-diaminopyrimidine
ALK protein, human
Alk protein, mouse
Alk protein, rat
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases