We report here that a tetra-substituted naphthalene-diimide derivative (MM41) has significant in vivo anti-tumour activity against the MIA PaCa-2 pancreatic cancer xenograft model. IV administration with a twice-weekly 15 mg/kg dose produces ca 80% tumour growth decrease in a group of tumour-bearing animals. Two animals survived tumour-free after 279 days. High levels of MM41 are rapidly transported into cell nuclei and were found to accumulate in the tumour. MM41 is a quadruplex-interactive compound which binds strongly to the quadruplexes encoded in the promoter sequences of the BCL-2 and k-RAS genes, both of which are dis-regulated in many human pancreatic cancers. Levels of BCL-2 were reduced by ca 40% in tumours from MM41-treated animals relative to controls, consistent with BCL-2 being a target for MM41. Molecular modelling suggests that MM41 binds to a BCL-2 quadruplex in a manner resembling that previously observed in co-crystal structures with human telomeric quadruplexes. This supports the concept that MM41 (and by implication other quadruplex-targeting small molecules) can bind to quadruplex-forming promoter regions in a number of genes and down-regulate their transcription. We suggest that quadruplexes within those master genes that are up-regulated drivers for particular cancers, may be selective targets for compounds such as MM41.

• MeSH
• Gene Expression MeSH
• G-Quadruplexes MeSH
• Transcription, Genetic MeSH
• Imides chemistry   pharmacology   MeSH
• Injections, Intravenous MeSH
• Humans MeSH
• Mice, Nude MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Pancreatic Neoplasms drug therapy   genetics   metabolism   pathology   MeSH
• Naphthalenes chemistry   pharmacology   MeSH
• Promoter Regions, Genetic * MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors   chemistry   genetics   metabolism   MeSH
• Proto-Oncogene Proteins p21(ras) genetics   metabolism   MeSH
• Drug Administration Schedule MeSH
• Molecular Dynamics Simulation MeSH
• Tumor Burden drug effects   MeSH
• Xenograft Model Antitumor Assays MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH