Cancer Research UK Drug DNA Interactions Research Group, UCL Cancer Institute, 72 Huntley Street, London, WC1E 6BT, UK.
Spirogen Ltd, QMB Innovation Centre, 42 New Road, London, E1 2AX, UK.
Sci Rep. 2018 Jul 11;8(1):10479. doi: 10.1038/s41598-018-28533-4.
Synthetic pyrrolobenzodiazepine (PBD) dimers, where two PBD monomers are linked through their aromatic A-ring phenolic C8-positions via a flexible propyldioxy tether, are highly efficient DNA minor groove cross-linking agents with potent cytotoxicity. PBD dimer SG3199 is the released warhead component of the antibody-drug conjugate (ADC) payload tesirine (SG3249), currently being evaluated in several ADC clinical trials. SG3199 was potently cytotoxic against a panel of human solid tumour and haematological cancer cell lines with a mean GI of 151.5 pM. Cells defective in DNA repair protein ERCC1 or homologous recombination repair showed increased sensitivity to SG3199 and the drug was only moderately susceptible to multidrug resistance mechanisms. SG3199 was highly efficient at producing DNA interstrand cross-links in naked linear plasmid DNA and dose-dependent cross-linking was observed in cells. Cross-links formed rapidly in cells and persisted over 36 hours. Following intravenous (iv) administration to rats SG3199 showed a very rapid clearance with a half life as short as 8 minutes. These combined properties of cytotoxic potency, rapid formation and persistence of DNA interstrand cross-links and very short half-life contribute to the emerging success of SG3199 as a warhead in clinical stage ADCs.
合成吡咯并苯并二氮杂（PBD）二聚体，其中两个 PBD 单体通过其芳族 A 环上的酚 C8 位通过柔性丙二氧基键合连接，是高效的 DNA 小沟交联剂，具有很强的细胞毒性。PBD 二聚体 SG3199 是抗体药物偶联物（ADC）有效载荷 tesirine（SG3249）的释放弹头成分，目前正在几项 ADC 临床试验中进行评估。SG3199 对一组人类实体瘤和血液系统癌细胞系具有很强的细胞毒性，平均 GI 为 151.5 pM。在 DNA 修复蛋白 ERCC1 或同源重组修复有缺陷的细胞中，对 SG3199 的敏感性增加，并且该药物对多药耐药机制仅具有中度敏感性。SG3199 在线性裸质粒 DNA 中非常有效地产生 DNA 链间交联，并且在细胞中观察到剂量依赖性交联。交联在细胞中迅速形成，并持续超过 36 小时。SG3199 在大鼠中静脉注射后表现出非常快速的清除，半衰期短至 8 分钟。这些细胞毒性效力、DNA 链间交联的快速形成和持久性以及非常短的半衰期的综合特性，有助于 SG3199 作为临床阶段 ADC 中的弹头取得新的成功。
