{"entity":{"id":"topoisomerase-inhibitors","kind":"technology","name":"Topoisomerase-I inhibitors (and ADC payloads)","aka":[],"tldr":"Topoisomerase-I inhibitors jam the enzyme that untangles DNA during copying, causing double-strand breaks. As free drugs (irinotecan, topotecan) they are modest, but their analogues SN-38 and deruxtecan are the dominant antibody-drug conjugate payload class of the 2020s, active after taxane failure; cross-resistance between these ADCs is a growing problem.","summary":"Irinotecan and topotecan are modest as systemic agents. Their analogues SN-38 (sacituzumab govitecan), DXd/exatecan derivatives (T-DXd, Dato-DXd, HER3-DXd, I-DXd, R-DXd), and belotecan derivatives (sac-TMT) are the dominant ADC payload class of the 2020s: membrane-permeable for bystander killing, short half-life limiting systemic toxicity, and effective in taxane-resistant tumours. Cross-resistance between TOP1 ADCs is a growing clinical problem.","status":"standard-of-care","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Topoisomerase_inhibitor","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Topoisomerase_inhibitor"}],"tags":[],"related":[],"cancers":[],"sections":["chemotherapy","adcs"],"technologies":["adc"],"targets":[],"drugs":[],"companies":["dantari","pheon-therapeutics","profoundbio","sunesis"],"institutions":[],"pathways":[],"terms":["payload","bystander-effect"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"principle":"Stabilise the TOP1-DNA cleavage complex, causing replication-associated double-strand breaks.","strengths":["Bystander effect","Active after taxanes and anthracyclines"],"limitations":["Cross-resistance between TOP1-payload ADCs (SLFN11 loss, TOP1 mutations)","ILD with DXd; neutropenia and diarrhoea with SN-38"]},"route":"/technologies/topoisomerase-inhibitors/","neighbours":{"section":[{"id":"adcs","kind":"section","name":"Antibody-Drug Conjugates","route":"/fronts/adcs/"},{"id":"chemotherapy","kind":"section","name":"Chemotherapy","route":"/fronts/chemotherapy/"}],"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"high-potency-payload-synthesis","kind":"technology","name":"Payload-linker synthesis (high-potency API)","route":"/technologies/high-potency-payload-synthesis/"}],"company":[{"id":"dantari","kind":"company","name":"Dantari","route":"/companies/dantari/"},{"id":"pheon-therapeutics","kind":"company","name":"Pheon Therapeutics","route":"/companies/pheon-therapeutics/"},{"id":"profoundbio","kind":"company","name":"ProfoundBio","route":"/companies/profoundbio/"},{"id":"sunesis","kind":"company","name":"Sunesis 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