The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial
©2021 The Authors; Published by the American Association for Cancer Research..
PURPOSE: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738.
EXPERIMENTAL DESIGN: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer.
RESULTS: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway.
CONCLUSIONS: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.
| Errataetall: |
CommentOn: Clin Cancer Res. 2021 Dec 1;27(23):6279. - PMID 34853073 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:27 |
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| Enthalten in: |
Clinical cancer research : an official journal of the American Association for Cancer Research - 27(2021), 23 vom: 01. Dez., Seite 6500-6513 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Schwenzer, Hagen [VerfasserIn] |
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| Links: |
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Comment |
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Date Completed 14.01.2022 Date Revised 06.01.2023 published: Print-Electronic CommentOn: Clin Cancer Res. 2021 Dec 1;27(23):6279. - PMID 34853073 Citation Status MEDLINE |
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| doi: |
10.1158/1078-0432.CCR-21-1652 |
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| PPN (Katalog-ID): |
NLM33039357X |
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| 245 | 1 | 4 | |a The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial |
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| 500 | |a Date Revised 06.01.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentOn: Clin Cancer Res. 2021 Dec 1;27(23):6279. - PMID 34853073 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a ©2021 The Authors; Published by the American Association for Cancer Research. | ||
| 520 | |a PURPOSE: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738 | ||
| 520 | |a EXPERIMENTAL DESIGN: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer | ||
| 520 | |a RESULTS: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway | ||
| 520 | |a CONCLUSIONS: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
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| 700 | 1 | |a De Zan, Erica |e verfasserin |4 aut | |
| 700 | 1 | |a Elshani, Mustafa |e verfasserin |4 aut | |
| 700 | 1 | |a van Stiphout, Ruud |e verfasserin |4 aut | |
| 700 | 1 | |a Kudsy, Mary |e verfasserin |4 aut | |
| 700 | 1 | |a Morris, Josephine |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrari, Valentina |e verfasserin |4 aut | |
| 700 | 1 | |a Um, In Hwa |e verfasserin |4 aut | |
| 700 | 1 | |a Chettle, James |e verfasserin |4 aut | |
| 700 | 1 | |a Kazmi, Farasat |e verfasserin |4 aut | |
| 700 | 1 | |a Campo, Leticia |e verfasserin |4 aut | |
| 700 | 1 | |a Easton, Alistair |e verfasserin |4 aut | |
| 700 | 1 | |a Nijman, Sebastian |e verfasserin |4 aut | |
| 700 | 1 | |a Serpi, Michaela |e verfasserin |4 aut | |
| 700 | 1 | |a Symeonides, Stefan |e verfasserin |4 aut | |
| 700 | 1 | |a Plummer, Ruth |e verfasserin |4 aut | |
| 700 | 1 | |a Harrison, David J |e verfasserin |4 aut | |
| 700 | 1 | |a Bond, Gareth |e verfasserin |4 aut | |
| 700 | 1 | |a Blagden, Sarah P |e verfasserin |4 aut | |
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