Abstract
We previously disclosed the identification of cereblon modulator 3 (CC-885), with potent antitumor activity mediated through the degradation of GSPT1. We describe herein the structure-activity relationships for analogs of 3 with exploration of the structurally related dioxoisoindoline class. The observed activity of protein degradation could in part be rationalized through docking into the previously disclosed 3-CRBN-GSPT1 cocrystal ternary complex. For SAR that could not be rationalized through the cocrystal complex, we sought to predict SAR through a QSAR model developed in house. Through these analyses, selective protein degradation could be achieved between the two proteins of interest, GSPT1 and Aiolos.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Chemistry Techniques, Synthetic
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Drug Evaluation, Preclinical / methods
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Humans
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Ikaros Transcription Factor / chemistry
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Ikaros Transcription Factor / genetics
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Ikaros Transcription Factor / metabolism*
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Molecular Docking Simulation
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Multiple Myeloma
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Peptide Hydrolases / chemistry
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Peptide Hydrolases / metabolism
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Peptide Termination Factors / chemistry
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Peptide Termination Factors / genetics
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Peptide Termination Factors / metabolism*
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Phthalimides / chemistry
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Piperidones / chemistry
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Proteolysis / drug effects*
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Quantitative Structure-Activity Relationship*
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Ubiquitin-Protein Ligases / metabolism*
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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CRBN protein, human
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IKZF3 protein, human
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IL17RB protein, human
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Peptide Termination Factors
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Phthalimides
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Piperidones
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peptide-chain-release factor 3
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Ikaros Transcription Factor
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phthalimidine
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Ubiquitin-Protein Ligases
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Peptide Hydrolases
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glutarimide