SN-38
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| Names | |
|---|---|
| Preferred IUPAC name
(4S)-4,11-Diethyl-4,9-dihydroxy-1,4-dihydro-3H,14H-pyrano[3′,4′:6,7]indolizino[1,2-b]quinoline-3,14-dione | |
| Other names
7-Ethyl-10-hydroxycamptothecin | |
| Identifiers | |
3D model (JSmol) |
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| ChEBI | |
| ChEMBL | |
| ChemSpider | |
| ECHA InfoCard | 100.171.154 |
PubChem CID |
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| UNII | |
CompTox Dashboard (EPA) |
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| Properties | |
| C22H20N2O5 | |
| Molar mass | 392.411 g·mol−1 |
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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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.[1]
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.[2]
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.
Use in antibody-drug conjugates
[edit]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.[3]
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".[3]
Interactive pathway map
[edit]Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "IrinotecanPathway_WP229".
See also
[edit]- NK012, a nanodevice formulation of SN-38
- Sacituzumab govitecan, an antibody-drug conjugate that uses SN-38 as the cytotoxic drug.
References
[edit]- ↑ "CAMPTOSAR- irinotecan hydrochloride injection, solution Pharmacia & Upjohn Company LLC".
- ↑ O'Dwyer PJ, Catalano RB (October 2006). "Uridine diphosphate glucuronosyltransferase (UGT) 1A1 and irinotecan: practical pharmacogenomics arrives in cancer therapy". J. Clin. Oncol. 24 (28): 4534–8. doi:10.1200/JCO.2006.07.3031. PMID 17008691.
- 1 2 Jabbarzadeh Kaboli P, Shabani S, Sharma S, Partovi Nasr M, Yamaguchi H, Hung MC (April 2022). "Shedding light on triple-negative breast cancer with Trop2-targeted antibody-drug conjugates". American Journal of Cancer Research. 12 (4): 1671–1685. PMC 9077081. PMID 35530295.
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