GC-targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models.

TitleGC-targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models.
Publication TypeJournal Article
Year of Publication2013
AuthorsRahman KM, Jackson PJM, James CH, B Basu P, Hartley JA, de la Fuente M, Schätzlein A, Robson M, R Pedley B, Pepper C, Fox KR, Howard PW, Thurston DE
JournalJ Med Chem
Volume56
Issue7
Pagination2911-35
Date Published2013 Apr 11
ISSN1520-4804
KeywordsAnimals, Antineoplastic Agents, Benzodiazepines, Cell Line, Tumor, Disease Models, Animal, Drug Screening Assays, Antitumor, Fluorescence Resonance Energy Transfer, GC Rich Sequence, Humans, In Vitro Techniques, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Structure, NF-kappa B, Spectrometry, Mass, Electrospray Ionization
Abstract

DNA binding 4-(1-methyl-1H-pyrrol-3-yl)benzenamine (MPB) building blocks have been developed that span two DNA base pairs with a strong preference for GC-rich DNA. They have been conjugated to a pyrrolo[2,1-c][1,4]benzodiazepine (PBD) molecule to produce C8-linked PBD-MPB hybrids that can stabilize GC-rich DNA by up to 13-fold compared to AT-rich DNA. Some have subpicomolar IC50 values in human tumor cell lines and in primary chronic lymphocytic leukemia cells, while being up to 6 orders less cytotoxic in the non-tumor cell line WI38, suggesting that key DNA sequences may be relevant targets in these ultrasensitive cancer cell lines. One conjugate, 7h (KMR-28-39), which has femtomolar activity in the breast cancer cell line MDA-MB-231, has significant dose-dependent antitumor activity in MDA-MB-231 (breast) and MIA PaCa-2 (pancreatic) human tumor xenograft mouse models with insignificant toxicity at therapeutic doses. Preliminary studies suggest that 7h may sterically inhibit interaction of the transcription factor NF-κB with its cognate DNA binding sequence.

DOI10.1021/jm301882a
Alternate JournalJ. Med. Chem.
PubMed ID23514599
Grant ListC180/A1060 / / Cancer Research UK / United Kingdom