SG3199 是一种具有细胞毒性的 DNA 小沟链间交联 PDB 二聚体。SG3199 是 ADC 有效载荷 Tesirine (SG3249) 的组成成分。
SG3199 is a cytotoxic DNA minor groove interstrand crosslinking pyrrolobenzodiazepine (PDB) dimer. SG3199 is the released warhead component of the ADC payload Tesirine (SG3249)[1][2].
SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI50 of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair show increased sensitivity to SG3199 and the drug is only moderately susceptible to multidrug resistance mechanisms[1]. SG3199 is highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking is observed in cells[1].
The in vitro binding of [3H]-SG3199 to the plasma proteins of rat (Sprague Dawley), cynomolgus monkey and human at concentrations of 0.8, 5 and 50 ng/mL is determined. Plasma protein binding is high in all species; rat ～97%, cynomolgus monkey ～90% and human ～95%[1]. Following i.v. administration at 0.1 μg/kg, 0.5 μg/kg and 1 μg/kg, SG3199 shows a very rapid clearance in rats. In the 0.5 μg/kg and 1 μg/kg dose groups, the rapid clearance was between 1000 and 1500 mL/h/kg, with a T1/2 between 8 and 42 minutes[1].
[1]. John A Hartley, et al. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. Sci Rep. 2018 Jul 11;8(1):10479.
[2]. Francesca Zammarchi, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018 Mar 8;131(10):1094-1105.
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