title: Novel 2,4-diaminopyrimidines bearing tetrahydronaphthalenyl moiety against anaplastic lymphoma kinase (ALK): Synthesis, in vitro, ex vivo, and in vivo efficacy studies.
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.
authors.affiliation: College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 28644, Republic of Korea.
authors.forename: Dawn
authors.initials: D
authors.lastname: Song
authors.affiliation: Department of Chemistry, Korea University, Seoul 02841, Republic of Korea.
authors.forename: Minji
authors.initials: M
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.affiliation: 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.
authors.forename: Chang Soo
authors.initials: CS
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Chong Ock
authors.initials: CO
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: hyngrk@krict.re.kr.
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009281:Naphthalenes / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D011743:Pyrimidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: 2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Tetrahydronaphthalenyl