Abstract
KRAS-PDEδ protein-protein interaction represents an appealing target for cancer therapy. However, fast release of high-affinity inhibitors from PDEδ hampered drug binding affinity and antiproliferative activity. To overcome the limitations, the first proteolysis-targeting chimeric (PROTAC) small molecules targeting PDEδ were designed. By employment of PDEδ inhibitor deltazinone (2) and cereblon ligand pomalidomide (6), a series of potent PROTAC PDEδ degraders were obtained. The most promising compound 17f efficiently induced PDEδ degradation and demonstrated significantly improved antiproliferative potency in KRAS mutant SW480 cells. Compound 17f also achieved significant tumor growth inhibition in the SW480 colorectal cancer xenograft model. This proof-of-concept study provided a new strategy to validate the druggability of KRAS-PDEδ interaction and offered an effective lead compound for the treatment of KRAS mutant cancer.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Cell Line, Tumor
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Colorectal Neoplasms / drug therapy*
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Colorectal Neoplasms / genetics
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Cyclic Nucleotide Phosphodiesterases, Type 6 / antagonists & inhibitors*
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Cyclic Nucleotide Phosphodiesterases, Type 6 / metabolism
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Drug Design
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Female
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Humans
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Male
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Mice, Inbred BALB C
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Molecular Structure
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Mutation
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Phosphodiesterase Inhibitors / chemical synthesis
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Phosphodiesterase Inhibitors / therapeutic use*
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Proteolysis / drug effects
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Proto-Oncogene Proteins p21(ras) / genetics
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Pyrazoles / chemical synthesis
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Pyrazoles / therapeutic use*
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Pyridazines / chemical synthesis
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Pyridazines / therapeutic use*
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Rats, Sprague-Dawley
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Structure-Activity Relationship
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Ubiquitin-Protein Ligases / metabolism
Substances
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KRAS protein, human
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Phosphodiesterase Inhibitors
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Pyrazoles
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Pyridazines
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Ubiquitin-Protein Ligases
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Cyclic Nucleotide Phosphodiesterases, Type 6
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Hras protein, mouse
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Proto-Oncogene Proteins p21(ras)