SN-38
Chemical compound
SN-38 is an antineoplastic drug. It is the active metabolite of irinotecan (an analog of camptothecin - a topoisomerase I inhibitor) but has 1000 times more activity than irinotecan itself. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold.
SN38 is formed via hydrolysis of irinotecan by carboxylesterases and metabolized via glucuronidation by UGT1A1.
The variant of UGT1A1 in ~10% of Caucasians which leads to poor metabolism of SN-38 predicts irinotecan toxicity, as it is then less easily excreted from the body in its SN-38 glucuronide form.
SN-38 and its glucuronide are lost into the bile and intestines. It can cause the symptoms of diarrhoea and myelosuppression experienced by ~25% of the patients administered irinotecan.
01Use in antibody-drug conjugates
SN-38 has been utilized as the cytotoxic payload in the antibody-drug conjugate (ADC) sacituzumab govitecan. Unlike ADCs that employ ultra-toxic payloads with picomolar IC50 values, SN-38 is considered a moderately toxic agent with IC50 in the nanomolar range, potentially allowing for a lower off-target toxicity profile.
In sacituzumab govitecan, SN-38 is conjugated to an anti-Trop2 antibody via a cleavable CL2A linker, achieving a high drug-to-antibody ratio (DAR) of approximately 7.6. This high DAR allows for efficient delivery of the chemotherapeutic agent to tumor cells. The cleavable linker also facilitates the release of SN-38 in both the extracellular space and the cytoplasm. Once released, SN-38's membrane permeability enables it to diffuse out of target cancer cells and exert cytotoxic effects on neighboring cells regardless of their Trop2 expression status, a phenomenon known as the "bystander killing effect".
02Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
Sources and credits
This article is adapted from the Wikipedia article “SN-38”, written by its contributors and licensed under CC BY-SA 4.0. Fathomly has changed the layout, removed citation markers, navigation and maintenance notices, and adjusted punctuation. This adapted version is shared under the same license. For references, see the original article.
Images, from Wikimedia Commons:
- SN-38.svg by Fvasconcellos, Public domain
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