Divinylsulfonamides enable the construction of homogeneous antibody–drug conjugates. Issue 23 (1st December 2020)

• Record Type: Journal Article
• Authors: Huang, Rong; Sheng, Yao; Wei, Ding; Lu, Wenwen; Xu, Zili; Chen, Hongli; Jiang, Biao
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 23(2020)
• Publication Date: 2020-12-01
• Subjects: Divinylsulfonamides -- Antibody-drug conjugates -- Selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2020.115793
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Methods that site-specifically attach payloads to an antibody with controlled DAR (Drug-Antibody Ratio) are highly desirable for the generation of homogeneous antibody-drug conjugates (ADCs). We describe the use of N -phenyl-divinylsulfonamide scaffold as a linker platform to site-specifically construct homogeneous DAR four ADCs through a disulfide re-bridging approach. Several monomethyl auristatin E (MMAE)-linkers were synthesized and the drug-linkers that contain electron-donating groups on the phenyl of the linker showed high stability. Her2-targeted MMAE-linker-herceptin and EGFR targeted MMAE-linker-cetuximab conjugates were prepared. The conjugates demonstrated high efficacy and selectivity for killing target-positive cancer cells in vitro . The EGFR-targeted conjugates also showed significant antitumor activities in vivo .