PMID- 26712094 OWN - NLM STAT- MEDLINE DCOM- 20160822 LR - 20181202 IS - 1464-3391 (Electronic) IS - 0968-0896 (Linking) VI - 24 IP - 2 DP - 2016 Jan 15 TI - Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors. PG - 207-19 LID - S0968-0896(15)30172-3 [pii] LID - 10.1016/j.bmc.2015.12.004 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Achary, Raghavendra AU - Achary R AD - 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. FAU - Yun, Jeong In AU - Yun JI AD - 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. FAU - Park, Chi Min AU - Park CM AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. FAU - Mathi, Gangadhar Rao AU - Mathi GR AD - 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. FAU - Lee, Joo Yun AU - Lee JY AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. FAU - Ha, Jae Du AU - Ha JD AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. FAU - Chae, Chong Hak AU - Chae CH AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. FAU - Ahn, Sunjoo AU - Ahn S AD - 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. FAU - Park, Chi Hoon AU - Park CH AD - 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. FAU - Lee, Chong Ock AU - Lee CO AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. FAU - Hwang, Jong Yeon AU - Hwang JY AD - 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. FAU - Yun, Chang-Soo AU - Yun CS AD - 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. FAU - Jung, Hee Jung AU - Jung HJ AD - 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. FAU - Cho, Sung Yun AU - Cho SY AD - 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. FAU - Kim, Hyoung Rae AU - Kim HR AD - Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: hyungrk@krict.re.kr. FAU - Kim, Pilho AU - Kim P AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151207 PL - England TA - Bioorg Med Chem JT - Bioorganic & medicinal chemistry JID - 9413298 RN - 0 (Antineoplastic Agents) RN - 0 (Pyrimidines) RN - 0 (Tetrahydroisoquinolines) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Alk protein, mouse) RN - EC 2.7.10.1 (Alk protein, rat) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) SB - IM MH - Anaplastic Lymphoma Kinase MH - Animals MH - Antineoplastic Agents/chemical synthesis/chemistry/*pharmacology MH - Cell Survival/drug effects MH - Dose-Response Relationship, Drug MH - *Drug Discovery MH - Female MH - Humans MH - Mice MH - Mice, Nude MH - Microsomes, Liver/drug effects/metabolism MH - Models, Molecular MH - Molecular Structure MH - Neoplasms, Experimental/drug therapy/pathology MH - Pyrimidines/chemical synthesis/chemistry/*pharmacology MH - Rats MH - Receptor Protein-Tyrosine Kinases/*antagonists & inhibitors/metabolism MH - Structure-Activity Relationship MH - Tetrahydroisoquinolines/chemistry/*pharmacology MH - Xenograft Model Antitumor Assays OTO - NOTNLM OT - ALK OT - Cancer OT - LDK378 OT - NSCLC OT - Tetrahydroisoquinoline (THIQ) EDAT- 2015/12/30 06:00 MHDA- 2016/08/23 06:00 CRDT- 2015/12/30 06:00 PHST- 2015/10/08 00:00 [received] PHST- 2015/11/18 00:00 [revised] PHST- 2015/12/02 00:00 [accepted] PHST- 2015/12/30 06:00 [entrez] PHST- 2015/12/30 06:00 [pubmed] PHST- 2016/08/23 06:00 [medline] AID - S0968-0896(15)30172-3 [pii] AID - 10.1016/j.bmc.2015.12.004 [doi] PST - ppublish SO - Bioorg Med Chem. 2016 Jan 15;24(2):207-19. doi: 10.1016/j.bmc.2015.12.004. Epub 2015 Dec 7.