DNA Topoisomerase 1 (TOP1) (TOP1)

DNA Topoisomerase 1 (TOP1) is a critical nuclear enzyme that regulates the topological state of DNA by inducing transient single-strand breaks, allowing the DNA to rotate and relieve torsional strain during replication and transcription (UniProt P11387). In cancer cells, TOP1 is often overexpressed to support rapid proliferation, making it a significant therapeutic target. Deruxtecan (DXd) is a potent, exatecan-derivative payload that specifically inhibits TOP1 by stabilizing the covalent TOP1-DNA inhibitory complex. This stabilization prevents DNA ligation, resulting in lethal double-strand breaks when the replication fork encounters the complex, ultimately triggering programmed cell death (Ogitani et al., 2016, Cancer Sci). As a payload in antibody-drug conjugates (ADCs) like Trastuzumab deruxtecan, deruxtecan allows for the targeted delivery of this cytotoxic effect to specific tumor cells, minimizing systemic toxicity while maximizing anti-tumor activity through its high potency and bystander killing effect (Nakada et al., 2019, Chem Pharm Bull).

Other names

Topoisomerase ITOP1DNA topoisomerase IType I DNA topoisomerase

Deruxtecan is a camptothecin derivative that acts as a DNA topoisomerase 1 (TOP1) inhibitor. It binds to and stabilizes the covalent TOP1-DNA complex (cleavable complex), preventing DNA re-ligation. This leads to the formation of double-strand DNA breaks when the replication fork collides with the stabilized complex, ultimately triggering apoptosis (Ogitani et al., 2016, Cancer Sci; Nakada et al., 2019, Chem Pharm Bull).