Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Frankowski, Kevin J.; Wang, Chen; Patnaik, Samarjit; Schoenen, Frank J.; Southall, Noel; Li, Dandan; Teper, Yaroslav; Sun, Wei; Kandela, Irawati; Hu, Deqing; Dextras, Christopher; Knotts, Zachary; Bian, Yansong; Norton, John T.; Titus, Steve; Lewandowska, Marzena Anna; Wen, Yiping; Farley, Katherine I.; Griner, Lesley Mathews; Sultan, Jamey; Meng, Zhaojing; Zhou, Ming; Vilimas, Tomas; Powers, Astin S.; Kozlov, Serguei; Nagashima, Kunio; Quadri, Humair S.; Fang, Min; Long, Charles D.; Khanolkar, Ojus; Chen, Warren; Kang, Jinsol; Huang, Helen Q.; Chow, Eric D.; Goldberg, Esthermanya; Feldman, C.; Xi, R.; Kim, Hye Rim; Sahagian, G. Gary; Baserga, Susan J.; Mazar, Andrew P.; Ferrer, Marc; Zheng, Wei; Shilatifard, Ali; Aubé, Jeffrey; Rudloff, Udo; Marugán, Juan; Huang, Sui

doi:10.1126/scitranslmed.aap8307

Cited by 63 publications

(62 citation statements)

References 76 publications

(119 reference statements)

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“…The prevalence of PNC bodies (expressed as the fraction of cells containing one or more PNCs) was 38.2% in untreated murine KPC tumors (Fig. 4a) which was similar to the PNC prevalence in the previously examined NOD/IL2 gamma (null) PANC1 metastasis model (35.1%) and higher than in cancer cell lines derived from primary pancreatic tumors (average ~ 23.5%) [15]. After 14-day treatment with 25 mg/kg metarrestin by oral gavage, PNC prevalence in KPC tumors was reduced to 9.8% (Fig.…”

Section: Resultssupporting

confidence: 80%

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

Vilimas

Wang

Patnaik

et al. 2018

Cancer Chemother Pharmacol

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PurposeMetarrestin is a first-in-class small molecule clinical candidate capable of disrupting the perinucleolar compartment, a subnuclear structure unique to metastatic cancer cells. This study aims to define the pharmacokinetic (PK) profile of metarrestin and the pharmacokinetic/pharmacodynamic relationship of metarrestin-regulated markers.MethodsPK studies included the administration of single or multiple dose of metarrestin at 3, 10, or 25 mg/kg via intravenous (IV) injection, gavage (PO) or with chow to wild-type C57BL/6 mice and KPC mice bearing autochthonous pancreatic tumors. Metarrestin concentrations were analyzed by UPLC–MS/MS. Pharmacodynamic assays included mRNA expression profiling by RNA-seq and qRT-PCR for KPC mice.ResultsMetarrestin had a moderate plasma clearance of 48 mL/min/kg and a large volume of distribution of 17 L/kg at 3 mg/kg IV in C57BL/6 mice. The oral bioavailability after single-dose (SD) treatment was > 80%. In KPC mice treated with SD 25 mg/kg PO, plasma AUC0–∞ of 14400 ng h/mL, Cmax of 810 ng/mL and half-life (t1/2) of 8.5 h were observed. At 24 h after SD of 25 mg/kg PO, the intratumor concentration of metarrestin was high with a mean value of 6.2 µg/g tissue (or 13 µM), well above the cell-based IC50 of 0.4 µM. At multiple dose (MD) 25 mg/kg/day PO in KPC mice, mean tissue/plasma AUC0–24h ratio for tumor, spleen and liver was 37, 30 and 31, respectively. There was a good linear relationship of dosage to AUC0–24h and C24h. AUC0–24h MD to AUC0–24h SD ratios ranged from two for liver to five for tumor indicating additional accumulation in tumors. Dose-dependent normalization of FOXA1 and FOXO6 mRNA expression was observed in KPC tumors.ConclusionsMetarrestin is an effective therapeutic candidate with a favorable PK profile achieving excellent intratumor tissue levels in a disease with known poor drug delivery.Electronic supplementary materialThe online version of this article (10.1007/s00280-018-3699-0) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 80%

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

Vilimas

Wang

Patnaik

et al. 2018

Cancer Chemother Pharmacol

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“…Suppression of Pol I activity partially recapitulates the effect of Metarrestin, although the drug does not induce genotoxic stress in cells. Remarkably, Metarrestin proved to be very effective in vivo, as it substantially blocked formation of metastasis in both xenograft and PDX tumor models, without displaying adverse effects in healthy animals [14].…”

Section: Advances In Cancermentioning

confidence: 99%

The cell nucleus. A study in Burgundy

Demidov

Aksenova

Dasso

et al. 2019

Nucleus

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Wilhelm Bernhard's revolutionary microscopy techniques helped him put forward the hypothesis of specialized compartmentalization of the nucleus. He also described for the first time the nuclear bodies and peri-chromatin fibrils, and demonstrated that these granules contain an RNA component. The tradition of biennial workshops, named after this great scientist, continues, and this year it took place in the heart of Burgundy, in Dijon, France (May 20-24, 2019, organized by INSERM UMR1231, UBFC), where well-fed participants emphasized the importance of viewing the cell nucleus as a hub of specialized colloidal compartments that orchestrate replication, transcription and nuclear transport.

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“…One of the recent additions to the RNA polymerase inhibitors is metarrestin which functions by impairing Pol I-ribosomal DNA interaction and inhibiting the function of Pol I (Frankowski et al, 2018). It also inhibits the transcription of Pol I and disrupts the function of the perinuclear compartment which is a complex nuclear structure associated with metastatic cancer.…”

Section: Metarrestinmentioning

confidence: 99%

Transcription and Translation Inhibitors in Cancer Treatment

et al. 2020

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Transcription and translation are fundamental cellular processes that govern the protein production of cells. These processes are generally up regulated in cancer cells, to maintain the enhanced metabolism and proliferative state of these cells. As such cancerous cells can be susceptible to transcription and translation inhibitors. There are numerous druggable proteins involved in transcription and translation which make lucrative targets for cancer drug development. In addition to proteins, recent years have shown that the "undruggable" transcription factors and RNA molecules can also be targeted to hamper the transcription or translation in cancer. In this review, we summarize the properties and function of the transcription and translation inhibitors that have been tested and developed, focusing on the advances of the last 5 years. To complement this, we also discuss some of the recent advances in targeting oncogenes tightly controlling transcription including transcription factors and KRAS. In addition to natural and synthetic compounds, we review DNA and RNA based approaches to develop cancer drugs. Finally, we conclude with the outlook to the future of the development of transcription and translation inhibitors.

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Metarrestin, a perinucleolar compartment inhibitor, effectively suppresses metastasis

Cited by 63 publications

References 76 publications

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

Pharmacokinetic evaluation of the PNC disassembler metarrestin in wild-type and Pdx1-Cre;LSL-KrasG12D/+;Tp53R172H/+ (KPC) mice, a genetically engineered model of pancreatic cancer

The cell nucleus. A study in Burgundy

Transcription and Translation Inhibitors in Cancer Treatment

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