2. Academic Validation
  3. Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors

Discovery of novel tetrahydroisoquinoline-containing pyrimidines as ALK inhibitors

  • Bioorg Med Chem. 2016 Jan 15;24(2):207-19. doi: 10.1016/j.bmc.2015.12.004.
Raghavendra Achary 1,  Jeong In Yun 2,  Chi Min Park 3,  Gangadhar Rao Mathi 1,  Joo Yun Lee 3,  Jae Du Ha 3,  Chong Hak Chae 3,  Sunjoo Ahn 1,  Chi Hoon Park 1,  Chong Ock Lee 3,  Jong Yeon Hwang 1,  Chang-Soo Yun 1,  Hee Jung Jung 1,  Sung Yun Cho 1,  Hyoung Rae Kim 4,  Pilho Kim 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
  • 4 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: hyungrk@krict.re.kr.
  • 5 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.
PMID: 26712094 DOI: 10.1016/j.bmc.2015.12.004
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.

Keywords

ALK; Cancer; LDK378; NSCLC; Tetrahydroisoquinoline (THIQ).

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