Systematic Variation of Pyrrolobenzodiazepine (PBD)-Dimer Payload Physicochemical Properties Impacts Efficacy and Tolerability of the Corresponding Antibody–Drug Conjugates

• Published in: Journal of medicinal chemistry Vol. 63; no. 17; pp. 9603 - 9622
• Main Authors: Staben, Leanna R, Chen, Jinhua, Cruz-Chuh, Josefa dela, del Rosario, Geoff, Go, Mary Ann, Guo, Jun, Khojasteh, S. Cyrus, Kozak, Katherine R, Li, Guangmin, Ng, Carl, Lewis Phillips, Gail D, Pillow, Thomas H, Rowntree, Rebecca K, Wai, John, Wei, BinQing, Xu, Keyang, Xu, Zijin, Yu, Shang-Fan, Zhang, Donglu, Dragovich, Peter S
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 10.09.2020; Amer Chemical Soc
• Subjects: Benzodiazepines - chemistry; Binding Sites; Cell Line, Tumor; Cell Proliferation - drug effects; Chemical Phenomena; Chemistry, Medicinal; Dimerization; DNA - chemistry; DNA - metabolism; Humans; Immunoconjugates - adverse effects; Immunoconjugates - chemistry; Immunoconjugates - metabolism; Immunoconjugates - pharmacology; Life Sciences & Biomedicine; Models, Molecular; Nucleic Acid Conformation; Pharmacology & Pharmacy; Pyrroles - chemistry; Safety; Science & Technology; CANCER-CELLS; TARGET; DIMER; POTENCY; DNA; CROSS-LINKING; RELEASE

Cytotoxic pyrrolobenzodiazepine (PBD)-dimer molecules are frequently utilized as payloads for antibody–drug conjugates (ADCs), and many examples are currently in clinical development. In order to further explore this ADC payload class, the physicochemical properties of various PBD-dimer molecules we...