Tumor Xenograft Uptake of a Pyrrole–Imidazole (Py-Im) Polyamide Varies as a Function of Cell Line Grafted

Raskatov, Jevgenij A.; Szablowski, Jerzy O.; Dervan, Peter B.

doi:10.1021/jm500964c

Cited by 19 publications

(11 citation statements)

References 36 publications

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“…In contrast to traditional cytotoxic chemotherapies, which crudely target growth processes shared by normal and cancerous tissues, agents such as imatinib mesylate (Gleevec) for BCR-ABL translocation that target genetic alterations underlying cancer often have mild toxicity because of their greater specificity for cancer cells 23 . In addition to specificity to the cancer genome, PI polyamide has been reported to accumulate specifically in xenografted tumour tissue in some cases 24 . These unique properties of PI polyamide conjugates provide a very efficient capacity for drug delivery, and its alkylating conjugate, which targets oncogenic somatic mutations, could reveal a superb selective advantage by specifically targeting cancer cells with the mutation.…”

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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“…The organ‐accumulation is a disturbing factor given the chance for higher levels of toxicity. Interestingly in another study, LNCaP xenograft‐bearing mice had greater liver accumulation (and impaired clearance) of Ac‐PA1 than mice with A549 (lung) or U251 (brain) xenografts . Here, LNCaP xenografts were also found to have much greater localization (up to 5×) of the polyamide than the non‐PCa xenografts.…”

Section: Hairpin Polyamide Antagonists Of Ar‐dna Bindingmentioning

confidence: 66%

Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

Elshan¹,

Rettig

Jung³

2018

Medicinal Research Reviews

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Prostate cancer (PCa) is the second most common cause of cancer-related mortality in men in the United States. The androgen receptor (AR) and the physiological pathways it regulates are central to the initiation and progression of PCa. As a member of the nuclear steroid receptor family, it is a transcription factor with three distinct functional domains (ligand-binding domain [LBD], DNA-binding domain [DBD], and transactivation domain [TAD]) in its structure. All clinically approved drugs for PCa ultimately target the AR-LBD. Clinically active drugs that target the DBD and TAD have not yet been developed due to multiple factors. Despite these limitations, the last several years have seen a rise in the discovery of molecules that could successfully target these domains. This review aims to present and comprehensively discuss such molecules that affect AR signaling through direct or indirect interactions with the AR-TAD or the DBD. The compounds discussed here include hairpin polyamides, niclosamide, marine sponge-derived small molecules (eg, EPI compounds), mahanine, VPC compounds, JN compounds, and bromodomain and extraterminal domain inhibitors. We highlight the significant in vitro and in Med Res Rev. 2019;39:910-960. wileyonlinelibrary.com/journal/med 910 | -binding domain; LRP6, low-density lipoprotein receptor-related protein 6;MAPK, mitogen-activated protein kinase; mCRPC, metastatic castration-resistant prostate cancer; mTOR, mammalian target of rapamycin; NHR, nuclear hormone receptor; PARP, poly (ADP-ribose) polymerase; PCa, prostate cancer; PI3K, phosphatidylinositol-3 kinase; PPARγ, peroxisome-proliferatoractivated receptor-γ; PR, progesterone receptor; PSA, prostate-specific antigen; PTEN, phosphatase and tensin homolog; Py, N-methylpyrrole; RNAP2, RNA polymerase II; SAR, structure-activity relationship; SPOP, speckle-type POZ protein; STAT, signal transducer and activator of transcription; TAD, transactivation domain; TMPRSS, transmembrane protease serine 2. vivo data found for each compound and the apparent limitations and/or potential for further development of these agents as PCa therapies. K E Y W O R D S androgen receptor, androgen receptor degradation, androgen receptor signaling axis, androgen receptor DNA-binding domain, androgen receptor transactivation domain, castration-resistant prostate cancer, prostate cancer 1 | INTRODUCTION 1.1 | Physiologic role and regulation of the androgen receptor The androgen receptor (AR) is a ligand-activated DNA-binding transcription factor of 110 kDa molecular weight, which facilitates the expression of androgen-dependent gene products (Figure 1). 1,2 As a member of the steroid and nuclear hormone receptor (NHR) super family, it shares many structural and functional features with other receptors such as the glucocorticoid receptor (GR), estrogen receptor (ER), mineralocorticoid receptor, progesterone receptor (PR), and the vitamin D receptor. 3,4 The nuclear steroid receptors consist of three principal domains: (1) the carboxy-terminal ligandbinding domain (...

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“…This is well-corroborated with the fact that small conformational distortions are sufficient to retard RNA polymerase II [17] and potentially displace histones [44]. Evidence also suggests that lipophilicity of a PIP is associated in tumor-directed delivery in situ [22], albeit there may be some dependence on the type and origin of tumors [45]. We can thus potentially expand our synthetic repertoire to introduce novel modifications to the existing PIP design toolbox to incorporate these improvements, but there are still caveats to take note of, not to mention again that these assays may only have provided us with qualitative results.…”

Section: Defining and Evaluating "Off-target" Effectsmentioning

confidence: 76%

The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

Lin

Nagase

2020

Biomolecules

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The high sequence specificity of minor groove-binding N-methylpyrrole-N-methylimidazole polyamides have made significant advances in cancer and disease biology, yet there have been few comprehensive reports on their off-target effects, most likely as a consequence of the lack of available tools in evaluating genomic binding, an essential aspect that has gone seriously underexplored. Compared to other N-heterocycles, the off-target effects of these polyamides and their specificity for the DNA minor groove and primary base pair recognition require the development of new analytical methods, which are missing in the field today. This review aims to highlight the current progress in deciphering the off-target effects of these N-heterocyclic molecules and suggests new ways that next-generating sequencing can be used in addressing off-target effects.

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Tumor Xenograft Uptake of a Pyrrole–Imidazole (Py-Im) Polyamide Varies as a Function of Cell Line Grafted

Cited by 19 publications

References 36 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

Molecules targeting the androgen receptor (AR) signaling axis beyond the AR‐Ligand binding domain

The Road Not Taken with Pyrrole-Imidazole Polyamides: Off-Target Effects and Genomic Binding

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