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      Induced protein degradation of anaplastic lymphoma kinase (ALK) by proteolysis targeting chimera (PROTAC).

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          Abstract

          Recently, proteolysis targeting chimera (PROTAC) technology is highlighted in drug discovery area as a new therapeutic approach. PROTAC as a heterobifunctional molecule is comprised of two ligands, which recruit target protein and E3 ligase, respectively. To degrade the anaplastic lymphoma kinase (ALK) fusion protein, such as NPM-ALK or EML4-ALK, we generated several ALK-PROTAC molecules consisted of ceritinib, one of the ALK inhibitors, and ligand of von Hippel-Lindau (VHL) E3 ligase. Among these molecules, TD-004 effectively induced ALK degradation and inhibited the growth of ALK fusion positive cell lines, SU-DHL-1 and H3122. We also confirmed that TD-004 significantly reduced the tumor growth in H3122 xenograft model.

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          Author and article information

          Journal
          Biochem. Biophys. Res. Commun.
          Biochemical and biophysical research communications
          Elsevier BV
          1090-2104
          0006-291X
          Oct 28 2018
          : 505
          : 2
          Affiliations
          [1 ] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea; College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea.
          [2 ] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea.
          [3 ] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea d Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea. Electronic address: chpark@krict.re.kr.
          [4 ] Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea; Medicinal Chemistry and Pharmacology, Korea University of Science and Technology, Daejeon 305-350, Republic of Korea d Korea Chemical Bank, Korea Research Institute of Chemical Technology, PO Box 107, Daejeon, 305-600, Republic of Korea. Electronic address: jyhwang@krict.re.kr.
          Article
          S0006-291X(18)32108-9
          10.1016/j.bbrc.2018.09.169
          30274779

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