Development and Clinical Trials of Nucleic Acid Medicines for Pancreatic Cancer Treatment

Yamakawa, Keiko; Nakano‐Narusawa, Yuko; Hashimoto, Nozomi; Yokohira, Masanao; Matsuda, Yoko

doi:10.3390/ijms20174224

Cited by 38 publications

(41 citation statements)

References 56 publications

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“…However, because nucleic acidbased molecules are unable to passively penetrate into cells and subjected to rapid enzyme-mediated hydrolysis, significant challenges have hampered them from becoming clinically useful drugs, including safe and efficient cell delivery, metabolic stability [4], off-target effects [5], and potential immunogenicity [6]. To date, only 9 nucleic acid-based drugs that inhibit specific protein production in patients have been approved in the USA, and none of which are for cancer therapy [7,8]. Therefore, small molecules have been explored to reduce a protein in cells, which works at the post-translational level to cause its degradation.…”

Section: Introductionmentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

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Proteolysis-targeting chimera (PROTAC) has been developed to be a useful technology for targeted protein degradation. A bifunctional PROTAC molecule consists of a ligand (mostly small-molecule inhibitor) of the protein of interest (POI) and a covalently linked ligand of an E3 ubiquitin ligase (E3). Upon binding to the POI, the PROTAC can recruit E3 for POI ubiquitination, which is subjected to proteasome-mediated degradation. PROTAC complements nucleic acid-based gene knockdown/out technologies for targeted protein reduction and could mimic pharmacological protein inhibition. To date, PROTACs targeting~50 proteins, many of which are clinically validated drug targets, have been successfully developed with several in clinical trials for cancer therapy. This article reviews PROTAC-mediated degradation of critical oncoproteins in cancer, particularly those in hematological malignancies. Chemical structures, cellular and in vivo activities, pharmacokinetics, and pharmacodynamics of these PROTACs are summarized. In addition, potential advantages, challenges, and perspectives of PROTAC technology in cancer therapy are discussed.

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Section: Introductionmentioning

confidence: 99%

Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy

2020

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“…Both AMG 520 and MRTX849 seem to give better results with combination of either upstream or downstream kinase inhibitors. This is not surprising as such, but more surprising is a very recent report concerning the rapid nonuniform adaptation to KRAS G12C inhibition (Xue et al, 2020). According to Xue et al (2020) G12C inhibitors targeting the RAS-GDP state promote a feedback mechanism in which KRAS G12C is maintained in active state by EGFR and Aurora kinase A (AURKA) signaling.…”

Section: Ras Inhibitorsmentioning

confidence: 98%

“…This is not surprising as such, but more surprising is a very recent report concerning the rapid nonuniform adaptation to KRAS G12C inhibition (Xue et al, 2020). According to Xue et al (2020) G12C inhibitors targeting the RAS-GDP state promote a feedback mechanism in which KRAS G12C is maintained in active state by EGFR and Aurora kinase A (AURKA) signaling. If this finding is validated it would indicate that EGFR and/or AURKA inhibition are mandatory to support and maintain KRAS G12C inhibition.…”

Section: Ras Inhibitorsmentioning

confidence: 98%

“…The power of ASOs as therapeutic agents has long been realized with FDA approval of the first ASO already in 1998 and 5 approved to date for nervous muscular or familial metabolic diseases (Stein and Castanotto, 2017;Yamakawa et al, 2019). However, antisense therapy for cancer treatment has lagged behind and to date there are no approved ASO therapeutic for cancer.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

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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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“…All these Authors thoroughly address and analyze from different perspectives the genomic, epigenetic, transcriptional, signaling, and metabolic levels at which the interplay occurs, on the grounds of a systematic and updated check of the evidence emerging from the related literature. Furthermore, Yamakawa et al [12] address the subject of the possible development of Clinical Trials of Nucleic Acid Medicine, and their delivery systems for Pancreatic Cancer. Of note, among the above quoted contributors, Zhang [9] points out the opportunity of Large-Scale Screenings and Artificial Intelligence-based technology to optimize the therapeutic approach, that is, in accordance with our considerations about complexity in the conclusive remarks.…”

mentioning

confidence: 99%