GC-Targeted C8-Linked pyrrolobenzodiazepine biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models

Rahman, K., Jackson, P., James, C., Basu, B., Hartley, J., de la Fuente, M., Schatzlein, A., Robson, M., Pedley, R., Pepper, Christopher John, Fox, K., Howard, P. and Thurston, D. 2013. GC-Targeted C8-Linked pyrrolobenzodiazepine biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models. Journal of Medicinal Chemistry 56 (7) , pp. 2911-2935. 10.1021/jm301882a

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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 IC 50 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine
Subjects:	R Medicine > R Medicine (General) R Medicine > RZ Other systems of medicine
Uncontrolled Keywords:	Animals; Antineoplastic Agents; Benzodiazepines; Cell Line Tumor; Disease Models Animal; Drug Screening Assays Antitumor; Fluorescence Resonance Energy Transfer; GC Rich Sequence; Humans; Magnetic Resonance Spectroscopy; Mice; Models Molecular; Molecular Structure; NF-kappa B; Spectrometry Mass Electrospray Ionization
Publisher:	American Chemical Society
ISSN:	0022-2623
Last Modified:	04 Jun 2017 08:18
URI:	https://orca.cardiff.ac.uk/id/eprint/75598

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