Arresting Cancer Proliferation by Small-Molecule Gene Regulation

Dickinson, Liliane A.; Burnett, Ryan; Melander, Christian; Edelson, Benjamin S.; Arora, Paramjit S.; Dervan, Peter B.; Gottesfeld, Joel M.

doi:10.1016/j.chembiol.2004.09.004

Cited by 77 publications

(110 citation statements)

References 38 publications

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“…The number of naked PI polyamides showing biological efficacy as single agents remains limited. Thus, one way to enhance the therapeutic potential of PI polyamides might be to conjugate them to small-molecule drugs, such as alkylating agents 21,22 .…”

Section: Discussionmentioning

confidence: 99%

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

et al. 2015

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Despite extensive efforts to target mutated RAS proteins, anticancer agents capable of selectively killing tumour cells harbouring KRAS mutations have remained unavailable. Here we demonstrate the direct targeting of KRAS mutant DNA using a synthetic alkylating agent (pyrrole-imidazole polyamide indole-seco-CBI conjugate; KR12) that selectively recognizes oncogenic codon 12 KRAS mutations. KR12 alkylates adenine N3 at the target sequence, causing strand cleavage and growth suppression in human colon cancer cells with G12D or G12V mutations, thus inducing senescence and apoptosis. In xenograft models, KR12 infusions induce significant tumour growth suppression, with low host toxicity in KRAS-mutated but not wild-type tumours. This newly developed approach may be applicable to the targeting of other mutant driver oncogenes in human tumours.

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Section: Discussionmentioning

confidence: 99%

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

et al. 2015

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“…1) changes the morphology of human SW620 colon carcinoma cells in culture, arrests proliferation at the G 2 /M phase of the cell cycle, and decreases histone H4c gene expression. 25 This molecule is also a potent inhibitor of tumor growth in a mouse xenograft model for human cancer. Among the 14 genes encoding histone H4 in the human genome, H4c is highly expressed in SW620 cells 25 and in several cancer cell lines in comparison to its expression in normal cells.…”

Section: Introductionmentioning

confidence: 99%

“…25 This molecule is also a potent inhibitor of tumor growth in a mouse xenograft model for human cancer. Among the 14 genes encoding histone H4 in the human genome, H4c is highly expressed in SW620 cells 25 and in several cancer cell lines in comparison to its expression in normal cells. 26 This observation accounts for the selectivity of 1R-Chl for cancer cells, and its low level of toxicity in mouse xenograft models 25 (and Alvarez et al, in preparation).…”

Section: Introductionmentioning

confidence: 99%

A Two-Hit Mechanism for Pre-Mitotic Arrest of Cancer Cell Proliferation by a Polyamide-Alkylator Conjugate

Álvarez¹,

Chou²,

Latella³

et al. 2006

Cell Cycle

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“…Polyamides have potent biological properties, ranging from selective targeting of viral DNA (5-7), derepression of developmental and disease-causing genes (8,9), and inhibition of tumor growth in vivo (10)(11)(12), to rational design of synthetic transcription factors (13)(14)(15)(16)(17)(18). Remarkably, rationally designed polyamides fed to Drosophila larvae induced classic homeotic patterns of developmental reprogramming (19).…”

mentioning

confidence: 99%

Synthetic genome readers target clustered binding sites across diverse chromatin states

Erwin

Grieshop

Bhimsaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Targeting the genome with sequence-specific DNA-binding molecules is a major goal at the interface of chemistry, biology, and precision medicine. Polyamides, composed of N-methylpyrrole and N-methylimidazole monomers, are a class of synthetic molecules that can be rationally designed to “read” specific DNA sequences. However, the impact of different chromatin states on polyamide binding in live cells remains an unresolved question that impedes their deployment in vivo. Here, we use cross-linking of small molecules to isolate chromatin coupled to sequencing to map the binding of two bioactive and structurally distinct polyamides to genomes directly within live H1 human embryonic stem cells. This genome-wide view from live cells reveals that polyamide-based synthetic genome readers bind cognate sites that span a range of binding affinities. Polyamides can access cognate sites within repressive heterochromatin. The occupancy patterns suggest that polyamides could be harnessed to target loci within regions of the genome that are inaccessible to other DNA-targeting molecules.

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Arresting Cancer Proliferation by Small-Molecule Gene Regulation

Abstract: and Chemical Engineering interfering with the transcription apparatus at promoter and enhancer elements [12, 13]. In contrast, polyamides

Cited by 77 publications

References 38 publications

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

Inhibition of KRAS codon 12 mutants using a novel DNA-alkylating pyrrole–imidazole polyamide conjugate

A Two-Hit Mechanism for Pre-Mitotic Arrest of Cancer Cell Proliferation by a Polyamide-Alkylator Conjugate

Synthetic genome readers target clustered binding sites across diverse chromatin states

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