The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
01 12 2021
01 12 2021
Historique:
received:
06
05
2021
revised:
04
07
2021
accepted:
02
09
2021
pubmed:
10
9
2021
medline:
15
1
2022
entrez:
9
9
2021
Statut:
ppublish
Résumé
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 We describe the synthesis of NUC-7738. We determine the IC 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 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.
Identifiants
pubmed: 34497073
pii: 1078-0432.CCR-21-1652
doi: 10.1158/1078-0432.CCR-21-1652
pmc: PMC9401491
doi:
Substances chimiques
Nucleosides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Comment
Langues
eng
Sous-ensembles de citation
IM
Pagination
6500-6513Subventions
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Commentaires et corrections
Type : CommentOn
Informations de copyright
©2021 The Authors; Published by the American Association for Cancer Research.
Références
Cell Cycle. 2015;14(5):761-71
pubmed: 25590866
Oncology (Williston Park). 2000 Jun;14(6 Suppl 2):31-5
pubmed: 10887642
Antimicrob Agents Chemother. 2014;58(4):1943-51
pubmed: 24419340
J Pharm Pharmacol. 2005 Dec;57(12):1509-19
pubmed: 16354395
Proc Natl Acad Sci U S A. 1970 Dec;67(4):1878-85
pubmed: 5275385
Mol Med Rep. 2019 Feb;19(2):901-908
pubmed: 30535479
Science. 2013 Apr 26;340(6131):479-83
pubmed: 23519211
Arch Pathol Lab Med. 2014 May;138(5):595-601
pubmed: 24236805
Nat Rev Immunol. 2018 May;18(5):309-324
pubmed: 29379212
Br J Cancer. 2018 Oct;119(7):815-822
pubmed: 30206366
Sci Rep. 2019 May 21;9(1):7643
pubmed: 31113993
Cancer Chemother Pharmacol. 2020 Jun;85(6):1011-1014
pubmed: 32476108
Sci Rep. 2019 Mar 18;9(1):4696
pubmed: 30886197
Cell Death Discov. 2018 May 23;4:62
pubmed: 29844932
Nat Methods. 2013 Oct;10(10):965-71
pubmed: 24161985
Life Sci. 2013 Nov 26;93(23):863-9
pubmed: 24121015
Oncogene. 2011 Apr 7;30(14):1615-30
pubmed: 21170083
Curr Protoc Nucleic Acid Chem. 2013 Jun;Chapter 15:15.5.1-15.5.15
pubmed: 23775807
RNA. 2012 Dec;18(12):2236-50
pubmed: 23118416
Sci Rep. 2019 Oct 31;9(1):15760
pubmed: 31673018
J Med Chem. 2011 Oct 27;54(20):7247-58
pubmed: 21892829
Med Oncol. 2020 Jun 11;37(7):61
pubmed: 32529264
Trends Biochem Sci. 2004 Feb;29(2):72-9
pubmed: 15102433
Onco Targets Ther. 2018 Aug 01;11:4479-4490
pubmed: 30122940
Cancer Res. 1977 Oct;37(10):3824-33
pubmed: 332340
Int J Oncol. 2013 Mar;42(3):1036-44
pubmed: 23292300
Future Oncol. 2020 Jun;16(16):1069-1081
pubmed: 32374623
J Med Chem. 2014 Feb 27;57(4):1531-42
pubmed: 24471998
Pharmacol Res Perspect. 2015 Mar;3(2):e00121
pubmed: 26038697
Genome Res. 2014 Dec;24(12):2059-65
pubmed: 25373145
Nat Rev Drug Discov. 2009 Jan;8(1):33-40
pubmed: 19116625
J Mol Model. 2020 Jan 17;26(2):29
pubmed: 31953681
J Agric Food Chem. 2010 Apr 28;58(8):4638-43
pubmed: 20302371
Phytochemistry. 2008 May;69(7):1469-95
pubmed: 18343466
Science. 2009 Nov 27;326(5957):1231-5
pubmed: 19965467
Toxicol Appl Pharmacol. 1997 Nov;147(1):39-45
pubmed: 9356305
Nucleosides Nucleotides Nucleic Acids. 2007;26(8-9):1121-4
pubmed: 18058549
Oncol Lett. 2015 Aug;10(2):595-599
pubmed: 26622539
Biochem Pharmacol. 2011 Sep 1;82(5):441-52
pubmed: 21658373
Int J Mol Sci. 2018 Oct 04;19(10):
pubmed: 30287757
Cell Death Dis. 2020 Mar 30;11(3):210
pubmed: 32231206
J Pharm Sci. 2012 Oct;101(10):3979-88
pubmed: 22833171
R Soc Open Sci. 2018 Dec 19;5(12):181247
pubmed: 30662735
Nature. 1950 Dec 2;166(4231):949
pubmed: 14796634
Cell Chem Biol. 2020 Feb 20;27(2):214-222.e4
pubmed: 31991096
Cold Spring Harb Perspect Biol. 2010 Jun;2(6):a000109
pubmed: 20516126
Cell Death Differ. 2001 Jun;8(6):621-30
pubmed: 11536013