Abstract
The first examples of threonine tyrosine kinase (TTK) PROTACs were designed and synthesized. Two of the most potent molecules, 8e and 8j, demonstrated strong TTK degradation in COLO-205 human colorectal cancer cells with DC50 values of 1.7 and 3.1 nM, respectively. Proteasome-mediated degradation by the compounds could last for approximately 8 h after washout. The degraders 8e and 8j demonstrated improved antiproliferative activities comparing with the structurally similar inhibitor counterparts 8q and 8r. Degraders 8e and 8j also demonstrated reasonable PK profiles and exhibited potent target degradation and in vivo anticancer efficacy in a xenograft mouse model of COLO-205 human colorectal cancer cells upon i.p. administration.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Design
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Humans
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Ligands
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Male
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Mice
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Mice, SCID
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Neoplasms / drug therapy
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Proteasome Endopeptidase Complex / metabolism
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Protein-Tyrosine Kinases / chemistry
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Protein-Tyrosine Kinases / metabolism*
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Proteolysis* / drug effects
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Structure-Activity Relationship
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Transplantation, Heterologous
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Von Hippel-Lindau Tumor Suppressor Protein / chemistry
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism
Substances
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Ligands
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Protein Kinase Inhibitors
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Von Hippel-Lindau Tumor Suppressor Protein
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Protein-Tyrosine Kinases
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Proteasome Endopeptidase Complex
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VHL protein, human