| Literature DB >> 34155147 |
K C Nicolaou1, Stephan Rigol2, Emmanuel N Pitsinos2,3, Dipendu Das2, Yong Lu2, Subhrajit Rout2, Alexander W Schammel4, Dane Holte4, Baiwei Lin5, Christine Gu5, Hetal Sarvaiya5, Jose Trinidad5, Nicole Barbour5, Amanda M Valdiosera5, Joseph Sandoval6, Christina Lee6, Monette Aujay6, Hanan Fernando7, Anukriti Dhar7, Holger Karsunky7, Nicole Taylor8, Marybeth Pysz8, Julia Gavrilyuk9.
Abstract
Antibody-drug conjugates (ADCs) have emerged as valuable targeted anticancer therapeutics with at least 11 approved therapies and over 80 advancing through clinical trials. Enediyne DNA-damaging payloads represented by the flagship of this family of antitumor agents, N-acetyl calicheamicin [Formula: see text], have a proven success track record. However, they pose a significant synthetic challenge in the development and optimization of linker drugs. We have recently reported a streamlined total synthesis of uncialamycin, another representative of the enediyne class of compounds, with compelling synthetic accessibility. Here we report the synthesis and evaluation of uncialamycin ADCs featuring a variety of cleavable and noncleavable linkers. We have discovered that uncialamycin ADCs display a strong bystander killing effect and are highly selective and cytotoxic in vitro and in vivo.Entities:
Keywords: antibody–drug conjugates; bystander killing effect; enediyne payloads
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Year: 2021 PMID： 34155147 PMCID： PMC8237573 DOI： 10.1073/pnas.2107042118
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205