Novel PIKK inhibitor antibody-drug conjugates: Synthesis and anti-tumor activity

[Display omitted] Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable lin...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2019-04, Vol.29 (7), p.943-947
Main Authors: Zhou, Dahui, Casavant, Jeffrey, Graziani, Edmund I., He, Haiyin, Janso, Jeffrey, Loganzo, Frank, Musto, Sylvia, Tumey, Nathan, O'Donnell, Christopher J., Dushin, Russell
Format: Article
Language:English
Subjects:
ADC
Aminoquinolines - chemical synthesis
Aminoquinolines - pharmacology
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - pharmacology
Antitumor
Cell Line, Tumor
Drug Screening Assays, Antitumor
HER2-expressing tumor cell lines
Humans
Immunoconjugates - pharmacology
Mutation
Neolymphostin
Phosphoinositide-3 Kinase Inhibitors - chemical synthesis
Phosphoinositide-3 Kinase Inhibitors - pharmacology
PIKK inhibitor
Proof of Concept Study
Pyrroles - chemical synthesis
Pyrroles - pharmacology
Trastuzumab - genetics
Trastuzumab - pharmacology
Trastuzumab conjugates
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Summary:[Display omitted] Novel neolymphostin-based antibody-drug conjugate (ADC) precursors were synthesized either through amide couplings between both cleavable and non-cleavable linkers and neolymphostin derivatives, or through Cu(I)-catalyzed acetylene-azide click cycloadditon between non-cleavable linkers and neolymphostin acetal derivatives. These precursors were site-specifically conjugated to cysteine mutant trastuzumab-A114C to provide neolymphostin-based ADCs. Preliminary in vitro data indicated that the corresponding ADCs were active against HER2-expressing tumor cell lines, thus providing a proof-of-concept for using neolymphostin as ADC-based anticancer agents.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2019.01.009