Duocarmycin DM

Duocarmycin DM is a synthetic DNA minor groove alkylator and a highly potent ADC cytotoxin utilized as an ADC payload in antibody-drug conjugates. Its cytotoxic mechanism involves sequence-specific alkylation of adenine residues within the minor groove of DNA, resulting in DNA strand stabilization, disruption of replication, and induction of apoptosis in proliferating tumor cells. The molecular structure of Duocarmycin DM allows covalent attachment to monoclonal antibodies via cleavable or non-cleavable linkers, facilitating targeted intracellular delivery in ADC applications.

Within antibody-drug conjugates, Duocarmycin DM is linked to antibodies using linker chemistries engineered to provide systemic stability while enabling controlled intracellular release. The ADC remains inactive in systemic circulation to reduce off-target cytotoxicity. After receptor-mediated internalization into antigen-expressing tumor cells, enzymatic or chemical cleavage releases the active Duocarmycin DM payload. Once released, it binds to DNA within the nucleus, causing replication arrest and triggering apoptosis. This targeted delivery ensures cytotoxic effects are confined to tumor cells, enhancing specificity and efficacy in tumor-targeted therapy.

Applications of Duocarmycin DM include incorporation into ADCs targeting both solid tumors and hematologic malignancies with defined antigen expression. Its chemical compatibility with diverse linker systems allows optimization of conjugation efficiency, intracellular release kinetics, and pharmacokinetic profiles. Duocarmycin DM exhibits potent cytotoxic activity in target-expressing cells, supporting the development of ADCs with controlled DNA alkylation and mechanistically precise antitumor effects. Its defined mode of action and predictable intracellular behavior make it suitable for rational ADC design and evaluation in preclinical and translational oncology research.