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

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 (A...

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Bibliographic Details
Published in:Biochemical and biophysical research communications 2018-10, Vol.505 (2), p.542-547
Main Authors: Kang, Chung Hyo, Lee, Dong Ho, Lee, Chong Ock, Du Ha, Jae, Park, Chi Hoon, Hwang, Jong Yeon
Format: Article
Language:English
Subjects:
60 APPLIED LIFE SCIENCES
Anaplastic lymphoma kinase
Cereblon
CHIMERAS
Degradation
Degrader
DRUGS
LIGASES
LYMPHOMAS
PHOSPHOTRANSFERASES
PROTEOLYSIS
Proteolysis targeting chimera
Von Hippel Lindau
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Summary: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.
ISSN:0006-291X
1090-2104
DOI:10.1016/j.bbrc.2018.09.169