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Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody-Drug Conjugates
- Source :
- Journal of medicinal chemistry. 63(17)
- Publication Year :
- 2020
-
Abstract
- Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody-drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules were modified by the systematic introduction of acidic and basic moieties into their chemical structures. The impact of these changes on DNA binding, cell membrane permeability, and in vitro antiproliferation potency was, respectively, determined using a DNA alkylation assay, PAMPA assessments, and cell-based cytotoxicity measurements conducted with a variety of cancer lines. The modified PBD-dimer compounds were subsequently incorporated into CD22-targeting ADCs, and these entities were profiled in a variety of in vitro and in vivo experiments. The introduction of a strongly basic moiety into the PBD-dimer scaffold afforded a conjugate with dramatically worsened mouse tolerability properties relative to ADCs derived from related payloads, which lacked the basic group.
- Subjects :
- Models, Molecular
Immunoconjugates
Chemical Phenomena
Pyrrolobenzodiazepine
behavioral disciplines and activities
chemistry.chemical_compound
Benzodiazepines
In vivo
Cell Line, Tumor
Drug Discovery
Moiety
Humans
Pyrroles
Binding site
Cytotoxicity
Cell Proliferation
Binding Sites
DNA
Combinatorial chemistry
In vitro
body regions
chemistry
Molecular Medicine
Nucleic Acid Conformation
Safety
Dimerization
Conjugate
Subjects
Details
- ISSN :
- 15204804
- Volume :
- 63
- Issue :
- 17
- Database :
- OpenAIRE
- Journal :
- Journal of medicinal chemistry
- Accession number :
- edsair.doi.dedup.....1f05642a14801d439bd63d27f4c631bb