Abstract
We previously discovered and validated a class of piperidinyl ureas that regulate defective in cullin neddylation 1 (DCN1)-dependent neddylation of cullins. Here, we report preliminary structure-activity relationship studies aimed at advancing our high-throughput screen hit into a tractable tool compound for dissecting the effects of acute DCN1-UBE2M inhibition on the NEDD8/cullin pathway. Structure-enabled optimization led to a 100-fold increase in biochemical potency and modestly increased solubility and permeability as compared to our initial hit. The optimized compounds inhibit the DCN1-UBE2M protein-protein interaction in our TR-FRET binding assay and inhibit cullin neddylation in our pulse-chase NEDD8 transfer assay. The optimized compounds bind to DCN1 and selectively reduce steady-state levels of neddylated CUL1 and CUL3 in a squamous cell carcinoma cell line. Ultimately, we anticipate that these studies will identify early lead compounds for clinical development for the treatment of lung squamous cell carcinomas and other cancers.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Carcinoma, Squamous Cell / drug therapy
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Cell Line, Tumor
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Crystallography, X-Ray
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Cullin Proteins / antagonists & inhibitors*
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Drug Discovery
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Drug Screening Assays, Antitumor
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High-Throughput Screening Assays
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Humans
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Intracellular Signaling Peptides and Proteins
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Lung Neoplasms / drug therapy
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Models, Molecular
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Molecular Conformation
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NEDD8 Protein / antagonists & inhibitors*
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NEDD8 Protein / metabolism
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Protein Binding
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Proteins
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Proto-Oncogene Proteins / antagonists & inhibitors*
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Proto-Oncogene Proteins / metabolism
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Signal Transduction / drug effects
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Structure-Activity Relationship
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Ubiquitin-Conjugating Enzymes / antagonists & inhibitors
Substances
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Antineoplastic Agents
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Cullin Proteins
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DCUN1D1 protein, human
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Intracellular Signaling Peptides and Proteins
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NEDD8 Protein
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NEDD8 protein, human
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Proteins
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Proto-Oncogene Proteins
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Ubiquitin-Conjugating Enzymes
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UBE2M protein, human