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

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

  • Biochem Biophys Res Commun. 2018 Oct 28;505(2):542-547. doi: 10.1016/j.bbrc.2018.09.169.
Chung Hyo Kang 1,  Dong Ho Lee 2,  Chong Ock Lee 2,  Jae Du Ha 2,  Chi Hoon Park 3,  Jong Yeon Hwang 4
Affiliations

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: [email protected].
  • 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: [email protected].
PMID: 30274779 DOI: 10.1016/j.bbrc.2018.09.169
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.

Keywords

Anaplastic lymphoma kinase; Cereblon; Degradation; Degrader; Proteolysis targeting chimera; Von Hippel Lindau.

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