title: Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors.
abstract: Exploration of the two-position side chain of pyrimidine in LDK378 with tetrahydroisoquinolines (THIQs) led to discovery of 8 and 17 as highly potent ALK inhibitors. THIQs 8 and 17 showed encouraging in vitro and in vivo xenograft efficacies, comparable with those of LDK378. Although THIQ analogs (8a-o and 17a-i) prepared were not as active as their parent compounds, both 8 and 17 have significant inhibitory activities against various ALK mutant enzymes including G1202R, indicating that this series of compounds could be further optimized as useful ALK inhibitors overcoming the resistance issues found from crizotinib and LDK378.
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
authors.forename: Raghavendra
authors.initials: R
authors.lastname: Achary
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon 305-764, Republic of Korea.
authors.forename: Jeong In
authors.initials: JI
authors.lastname: Yun
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Chi Min
authors.initials: CM
authors.lastname: Park
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
authors.forename: Gangadhar Rao
authors.initials: GR
authors.lastname: Mathi
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Joo Yun
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Jae Du
authors.initials: JD
authors.lastname: Ha
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
authors.forename: Chong Hak
authors.initials: CH
authors.lastname: Chae
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, 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 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, 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 305-600, 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 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
authors.forename: Jong Yeon
authors.initials: JY
authors.lastname: Hwang
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, 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 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
authors.forename: Hee Jung
authors.initials: HJ
authors.lastname: Jung
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
authors.forename: Sung Yun
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: hyungrk@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 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea. Electronic address: pkim@krict.re.kr.
authors.forename: Pilho
authors.initials: P
authors.lastname: Kim
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011743:Pyrimidines; D044005:Tetrahydroisoquinolines; C000626173:ALK protein, human; C000626174:Alk protein, mouse; C000626175:Alk protein, rat; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: ALK; Cancer; LDK378; NSCLC; Tetrahydroisoquinoline (THIQ)