Uncialamycin as a novel payload for antibody drug conjugate (ADC) based targeted cancer therapy. Issue 3 (1st February 2019)

• Record Type: Journal Article
• Authors: Chowdari, Naidu S.; Pan, Chin; Rao, Chetana; Langley, David R.; Sivaprakasam, Prasanna; Sufi, Bilal; Derwin, Daniel; Wang, Yichong; Kwok, Eilene; Passmore, David; Rangan, Vangipuram S.; Deshpande, Shrikant; Cardarelli, Pina; Vite, Gregory; Gangwar, Sanjeev
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 29:Issue 3(2019)
• Page Start: 466
• Page End: 470
• Publication Date: 2019-02-01
• Subjects: Antibody-drug conjugates -- Uncialamycin -- Peptide linker -- Lung cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.12.021
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Uncialamycin analogs were evaluated as potential cytotoxic agents in an antibody-drug conjugate (ADC) approach to treating human cancer. These analogs were synthesized using Hauser annulations of substituted phthalides as a key step. A highly potent uncialamycin analog 3c with a valine-citrulline dipeptide linker was conjugated to an anti-mesothelin monoclonal antibody (mAb) through lysines to generate a meso -13 conjugate. This conjugate demonstrated subnanomolar potency (IC50 = 0.88 nM, H226 cell line) in in vitro cytotoxicity experiments with good immunological specificity to mesothelin-positive lung cancer cell lines. The potency and mechanism of action of this uncialamycin class of enediyne antitumor antibiotics make them attractive payloads in ADC-based cancer therapy.