Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1<i>H</i>)-one Derivatives as Orally eIF4A3-Selective Inhibitors

Mizojiri, Ryo; Nakata, Daisuke; Satoh, Yoshihiko; Morishita, Daisuke; Shibata, Sachio; Iwatani-Yoshihara, Misa; Kosugi, Yukio; Kosaka, Mai; Takeda, Junpei; Sasaki, Shigekazu; Takami, Kazuaki; Fukuda, Koichiro; Kamaura, Masahiro; Sasaki, Shinobu; Arai, Ryosuke; Cary, Douglas R.; Imaeda, Yasuhiro

doi:10.1021/acsmedchemlett.7b00283

Cited by 12 publications

(16 citation statements)

References 33 publications

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“…Thus, several medicinal chemists are aiming to develop highly selective EIF4A3 inhibitors to identify the role of EIF4A3. Although research on EIF4A3 inhibitors is still in the preclinical stage, several potent EIF4A3 inhibitors (EIF4A3 inhibitor 1a, 53a, 1o and 1q) have been identified ( 46 , 48 , 49 ), and with further research, the molecular mechanism underlying EIF4A3 will be revealed. Thus, EIF4A3 may serve as a novel therapeutic target for cancer in the future.…”

Section: Discussionmentioning

confidence: 99%

“…A HCT-116 ×enograft mouse model was used to analyze the antitumor activity of 1o and 1q. The results demonstrated that 1o and 1q significantly inhibit the growth of transplanted tumors without severe weight loss of the xenograft mouse models ( 49 ). Further studies will identify additional EIF4A3 small molecule inhibitors for EJC and NMD, and for cancer targeted EIF4A3 treatment.…”

Section: Eif4a3 Inhibitorsmentioning

confidence: 97%

“…The IC 50 values of inhibitors 1o and 1q are 0.1 µM (0.06–0.15) and 0.14 µM (0.09–0.22), respectively. In addition, they both display NMD inhibition activity, which was identified by performing a luciferase based cellular NMD reporter assay ( 49 ). A HCT-116 ×enograft mouse model was used to analyze the antitumor activity of 1o and 1q.…”

Section: Eif4a3 Inhibitorsmentioning

confidence: 99%

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Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

Zhu

Ren

2021

Oncol Lett

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Eukaryotic translation initiation factor 4A3 (EIF4A3), a key component of the exon junction complex, is widely involved in RNA splicing and nonsense-mediated mRNA decay. EIF4A3 has also been reported to be involved in cell cycle regulation and apoptosis. Thus, EIF4A3 may serve as a pivotal regulatory factor involved in the occurrence and development of multiple diseases. Previous studies have demonstrated that EIF4A3 is mutated in neuromuscular degenerative lesions and is differentially expressed in several tumors, serving as a non-coding RNA binding protein to regulate its expression. In addition, studies have reported that inhibiting EIF4A3 can prevent tumor cell proliferation, thus, several researchers are trying to design and synthesize potent and selective EIF4A3 inhibitors. The present review summarizes the function of EIF4A3 in cell cycle and discusses it underlying molecular mechanisms that contribute to the occurrence of malignant diseases. In addition, EIF4A3 selective inhibitors, and bioinformatics analyses performed to analyze the expression and mutations of EIF4A3 in gynecological tumors and breast cancer, are also discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Eif4a3 Inhibitorsmentioning

confidence: 97%

Section: Eif4a3 Inhibitorsmentioning

confidence: 99%

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Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

Zhu

Ren

2021

Oncol Lett

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“…On the contrary, eIF4A3 mRNA levels have been found elevated in cancer ( 10 ), where the helicase regulates the expression and tumor-promoting activity of various noncoding RNAs including circular, micro-, or long noncoding RNAs ( 11 ). At the molecular level, eIF4A3 deficiency hinders cell migration and impairs cell viability ( 12 ), two aspects that inspired the development of eIF4A3 chemical inhibitors for cancer treatment ( 13 ). Notably, p53 ablation could only partially rescue the microcephaly of eIF4A3 haploinsufficient mice ( 8 ), leaving elusive the exact mechanisms of excessive cell death following reduced eIF4A3 expression, an intriguing issue addressed in our present study.…”

Section: Introductionmentioning

confidence: 99%

The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output

et al. 2021

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Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3’s tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint–mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3’s unexpected role in RiBi, with implications for cancer pathogenesis and treatment.

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“…Cancer cells are considered highly dependent on the NMD system in avoiding the accumulation of aberrant proteins (Gilboa, 2013). Therefore, some eIF4A3 inhibitors were developed as anti-cancer agents (Mizojiri et al, 2017). Meanwhile, eIF4A family members have been proved to be essential in HCMV virus growth.…”

Section: Discussionmentioning

confidence: 99%

Avian Influenza A Virus Polymerase Recruits Cellular RNA Helicase eIF4A3 to Promote Viral mRNA Splicing and Spliced mRNA Nuclear Export

Ren

et al. 2019

Front. Microbiol.

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The influenza A virus replicates in a broad range of avian and mammalian species by hijacking cellular factors and processes. Avian influenza A viruses (AIVs) generally propagated poorly in mammalian cells, but some mutants of virus-encoded RNA polymerase components, especially PB2 subunit, can overcome host restriction. Host factors associated with PB2 may be essential for efficient AIV replication in mammalian cells. Here, we infected human cells with the PB2 Flag-tagged replication-competent recombinant AIV and identified cellular proteins that coprecipitate with PB2 protein by mass spectrometry. We confirmed one of the coprecipitating host factors, DEAD-box protein eIF4A3, that interacts with viral PB2, PB1, and NP proteins. Depletion of endogenous eIF4A3 significantly reduced virus replication. Later studies showed that eIF4A3 is essential for viral RNA polymerase activity and viral RNAs synthesis. Upon systematic dissection of the influenza virus progeny mRNA generation, from pre-mRNA processing to nuclear export, we found that the depletion of eIF4A3 resulted in significant defects in the ratio of M2 to M1 and NS2 to NS1, and the proportion of viral spliced mRNA in the nucleus increased, indicating that eIF4A3 plays a significant function in viral nascent intron mRNA splicing and spliced mRNA (M2 and NS2) nuclear export. Additionally, we confirmed that in specific deletion of eIF4A3, the synthesis of reduced NS2 can significantly impair neo-synthetized viral ribonucleoprotein (vRNP) nuclear export. Taken together, our findings revealed that eIF4A3 is a key mediator of AIV polymerase activity, mRNA splicing, and spliced mRNA nuclear export.

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Discovery of Novel 5-(Piperazine-1-carbonyl)pyridin-2(1H)-one Derivatives as Orally eIF4A3-Selective Inhibitors

Cited by 12 publications

References 33 publications

Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

Effect of eukaryotic translation initiation factor 4A3 in malignant tumors (Review)

The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output

Avian Influenza A Virus Polymerase Recruits Cellular RNA Helicase eIF4A3 to Promote Viral mRNA Splicing and Spliced mRNA Nuclear Export

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