title: Novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety for anaplastic lymphoma kinase (ALK) inhibitor.
abstract: In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.
authors.affiliation: Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Achary
authors.affiliation: Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Gangadhar Rao
authors.initials: GR
authors.lastname: Mathi
authors.affiliation: Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Dong Ho
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, 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: Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Hyoung Rae
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
authors.forename: Chi Hoon
authors.initials: CH
authors.lastname: Park
authors.affiliation: Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: pkim@krict.re.kr.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
authors.affiliation: Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
mesh_terms: D000284:Administration, Oral; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use / Q000633:toxicity; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C017205:2,4-diaminopyrimidine; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: 2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Fused tricyclic moiety