title: GC-targeted C8-linked pyrrolobenzodiazepine-biaryl conjugates with femtomolar in vitro cytotoxicity and in vivo antitumor activity in mouse models.
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.
authors.affiliation: Department of Pharmacy, Institute of Pharmaceutical Sciences, King's College London, 150 Stamford Street, London SE1 9NH, United Kingdom.
authors.forename: Khondaker M
authors.initials: KM
authors.lastname: Rahman
authors.forename: Paul J M
authors.initials: PJ
authors.lastname: Jackson
authors.forename: Colin H
authors.initials: CH
authors.lastname: James
authors.forename: B Piku
authors.initials: BP
authors.lastname: Basu
authors.forename: John A
authors.initials: JA
authors.lastname: Hartley
authors.forename: Maria
authors.initials: M
authors.lastname: de la Fuente
authors.forename: Andreas
authors.initials: A
authors.lastname: Schatzlein
authors.forename: Mathew
authors.initials: M
authors.lastname: Robson
authors.forename: R Barbara
authors.initials: RB
authors.lastname: Pedley
authors.forename: Chris
authors.initials: C
authors.lastname: Pepper
authors.forename: Keith R
authors.initials: KR
authors.lastname: Fox
authors.forename: Philip W
authors.initials: PW
authors.lastname: Howard
authors.forename: David E
authors.initials: DE
authors.lastname: Thurston
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004354:Drug Screening Assays, Antitumor; D031541:Fluorescence Resonance Energy Transfer; D020862:GC Rich Sequence; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000970:Antineoplastic Agents; D016328:NF-kappa B; D001569:Benzodiazepines