Therapeutic gene regulation using pyrrole–imidazole polyamides

Yu, Zutao; Pandian, Ganesh N.; Hidaka, Takehiko; Sugiyama, Hiroshi

doi:10.1016/j.addr.2019.02.001

Cited by 36 publications

(26 citation statements)

References 200 publications

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“…Of particular interest is the quadruplex–duplex junction, which would provide a unique interface for ligand targeting ( 34 , 83 , 84 ). Conceptually, the two alternative QDH structures of PIM1 SLQS would be excellent targets for the pyrrole–imidazole polyamide (PIP) class of duplex minor groove-binding agents ( 76 , 78 , 79 ); the duplex stem and G-tetrad core are stacked against each other, thus presenting a continuous progression of the groove for accommodation of a ligand (Figure 6 ). PIPs have been successfully designed to selectively target Watson-Crick A•T, T•A, G•C and C•G base pair steps on the minor groove of a duplex stem.…”

Section: Resultsmentioning

confidence: 99%

Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Tan

Winnerdy

Lim

et al. 2020

Nucleic Acids Research

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The triple-negative breast cancer (TNBC), a subtype of breast cancer which lacks of targeted therapies, exhibits a poor prognosis. It was shown recently that the PIM1 oncogene is highly related to the proliferation of TNBC cells. A quadruplex–duplex hybrid (QDH) forming sequence was recently found to exist near the transcription start site of PIM1. This structure could be an attractive target for regulation of the PIM1 gene expression and thus the treatment of TNBC. Here, we present the solution structures of two QDHs that could coexist in the human PIM1 gene. Form 1 is a three-G-tetrad-layered (3+1) G-quadruplex containing a propeller loop, a lateral loop and a stem-loop made up of three G•C Watson–Crick base pairs. On the other hand, Form 2 is an anti-parallel G-quadruplex comprising two G-tetrads and a G•C•G•C tetrad; the structure has three lateral loops with the middle stem-loop made up of two Watson-Crick G•C base pairs. These structures provide valuable information for the design of G-quadruplex-specific ligands for PIM1 transcription regulation.

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Section: Resultsmentioning

confidence: 99%

Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Tan

Winnerdy

Lim

et al. 2020

Nucleic Acids Research

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“…The nanoparticles can also be targeted to the tumor by equipping with ligands that can target cancer receptors [ 4 ]. We have been interested in pyrrole–imidazole polyamide (PIP) compounds that can bind to minor grooves of DNA and shut down gene expression [ 5 , 6 ]. Interestingly, tumor accumulation of some PIP compounds has been reported [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Tumor Accumulation of PIP-Based KRAS Inhibitor KR12 Evaluated by the Use of a Simple, Versatile Chicken Egg Tumor Model

Higashi

Ikeda

Matsumoto

et al. 2022

Cancers

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Background: The KRAS inhibitor KR12, based on pyrrole-imidazole polyamide (PIP), has been developed and shown to exhibit efficacy in mouse experiments. Because some PIP species exhibit tumor accumulation capability, we decided to evaluate whether the PIP portion of KR12 exhibits tumor accumulation. We employed the CAM assay that provides a simple method for tumor accumulation evaluation. Methods: KR12 PIP was synthesized and conjugated to TAMRA to produce a fluorescently labeled reagent (KR12-TAMRA). This reagent was injected into a fertilized chicken egg that has been transplanted with human cancer cells. Distribution of the red fluorescence was examined by cutting out tumor as well as various organs from the embryo. Results: The red fluorescence of KR12-TAMRA was found to overlap with the green fluorescence of the tumor formed with GFP-expressing cancer cells. We also observed nuclear localization of KR12-TAMRA. Treatment of KR12 that contained the alkylating agent CBI in the tumor-bearing chicken egg resulted in tumor growth inhibition. Conclusions: KR12 contains a PIP that has two key features: tumor accumulation and nuclear localization. KR12 conjugated with CBI exhibits inhibition of tumor growth in the CAM model.

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“…Chemical conjugation of PI polyamides with various moieties, often referred to as PI polyamide‐drug conjugates (PDC), can expand their functional repertoire beyond simple minor groove base‐specific binding; these PDCs are capable of genomic manipulation down to the precision of a single nucleotide difference in vitro and in vivo. 14 Expanding upon this strategy of “genome instigators,” we and others around the world have designed and reported various PDCs that can target specific double‐stranded B‐form DNA sequences in the nuclear and mitochondrial genomes, as well as genomes of parasitic microbes to provide means of therapy, 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 as well as cancer diagnostic applications in the form of target enrichment from bodily fluid specimens. 25 …”

Section: Introductionmentioning

confidence: 99%

Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer

et al. 2021

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As the energy factory for the cell, the mitochondrion, through its role of adenosine triphosphate production by oxidative phosphorylation, can be regarded as the guardian of well regulated cellular metabolism; the integrity of mitochondrial functions, however, is particularly vulnerable in cancer due to the lack of superstructures such as histone and lamina folds to protect the mitochondrial genome from unintended exposure, which consequently elevates risks of mutation. In cancer, mechanisms responsible for enforcing quality control surveillance for identifying and eliminating defective mitochondria are often poorly regulated, and certain uneliminated mitochondrial DNA (mtDNA) mutations and polymorphisms can be advantageous for the proliferation, progression, and metastasis of tumor cells. Such pathogenic mtDNA aberrations are likely to increase and occasionally be homoplasmic in cancer cells and, intriguingly, in normal cells in the proximity of tumor microenvironments as well. Distinct characteristics of these abnormalities in mtDNA may provide a new path for cancer therapy. Here we discuss a promising novel therapeutic strategy, using the sequence‐specific properties of pyrrole‐imidazole polyamide‐triphenylphosphonium conjugates, against cancer for clearing abnormal mtDNA by reactivating mitochondrial quality control surveillance.

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Therapeutic gene regulation using pyrrole–imidazole polyamides

Cited by 36 publications

References 200 publications

Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Coexistence of two quadruplex–duplex hybrids in the PIM1 gene

Tumor Accumulation of PIP-Based KRAS Inhibitor KR12 Evaluated by the Use of a Simple, Versatile Chicken Egg Tumor Model

Mitochondria: Endosymbiont bacteria DNA sequence as a target against cancer

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