Indolinobenzodiazepine pseudodimer (IGN) DNA alkylator (IGN)

The indolinobenzodiazepine pseudodimer (IGN) DNA alkylator refers to a class of cytotoxic small molecules used as payloads in antibody–drug conjugates (ADCs) targeting cancers. Unlike the closely related pyrrolobenzodiazepine (PBD) dimers, which can cross-link DNA, IGNs possess a single reactive imine moiety and act by monoalkylating genomic DNA at guanine residues, typically from the DNA minor groove. This generates highly cytotoxic, stable DNA adducts that lead to irreparable DNA damage, cell cycle arrest, and apoptosis in target cells. IGNs are used in several clinical ADCs, including IMGN779, IMGN632, and TAK-164, designed to treat hematologic malignancies by targeting specific cell surface antigens like CD123. The use of a monoalkylating agent in IGNs, compared to cross-linking agents, is associated with improved tolerability and reduced myelosuppression, enabling higher or more sustained therapeutic dosing. Since IGNs are cytotoxins and not biological macromolecules, they are not considered "targets" in the classic pharmacological sense, but rather as payloads for targeted delivery systems.

Other names

IGN payloadindolinobenzodiazepine dimerIGN DNA monoalkylator

Covalent alkylation of DNA at guanine residues via a monoimine moiety (no cross-linking); leads to DNA damage, cell cycle arrest, and apoptosis