化学
药物开发
结合
组合化学
候选药物
二聚体
小分子
效力
药物发现
连接器
抗体
药品
色谱法
抗体-药物偶联物
药理学
体外
生物化学
单克隆抗体
有机化学
医学
计算机科学
免疫学
数学分析
操作系统
数学
作者
Dane Holte,M. Suri Appa Rao,Alexander D. Huters,Justin A. Simanis,Jean-Christophe Califano,Aaron Kempema,Jean-Noel Levy
标识
DOI:10.1021/acs.oprd.0c00497
摘要
Pyrrolobenzodiazepine (PBD) dimers, such as that found in SG3259, are fully synthetic highly potent (subnanomolar) small molecules currently being developed as warheads for antibody–drug conjugates (ADCs). The complete synthetic route toward the linker drug SG3259 has 17 steps, and 10–20 g of drug was needed prior to antibody conjugation for IND-enabling toxicological studies and Phase I clinical trials. Herein, we disclose the enabling route to SG3259, with the final four steps being conducted under GMP conditions. Significant effort was spent developing the preparatory scale reverse-phase HPLC purification of the final linker drug. SG3259 suffers from poor solubility; acid-, light-, and oxygen-sensitivity; and extremely high potency, factors which make this a challenging target for gram-scale development.
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