Abstract
Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines. High levels of in vitro potency and specificity were demonstrated with an anti-mesothelin conjugate.
Keywords:
Antibody-drug conjugates; Macrocycles; Pyrrolobenzodiazepines.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Antibodies / chemistry
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Antibodies / metabolism*
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Antineoplastic Agents / chemical synthesis
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology*
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Benzodiazepines / chemical synthesis
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Benzodiazepines / chemistry
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Benzodiazepines / pharmacology*
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Dimerization
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Dose-Response Relationship, Drug
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Drug Screening Assays, Antitumor
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Humans
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Molecular Structure
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Pyrroles / chemical synthesis
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Pyrroles / chemistry
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Pyrroles / pharmacology*
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Solubility
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Structure-Activity Relationship
Substances
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Antibodies
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Antineoplastic Agents
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Macrocyclic Compounds
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Pyrroles
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pyrrolo(2,1-c)(1,4)benzodiazepine
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Benzodiazepines