Discovery and Optimization of Pyrrolopyrimidine Derivatives as Selective Disruptors of the Perinucleolar Compartment, a Marker of Tumor Progression toward Metastasis.
Journal
Journal of medicinal chemistry
ISSN: 1520-4804
Titre abrégé: J Med Chem
Pays: United States
ID NLM: 9716531
Informations de publication
Date de publication:
23 06 2022
23 06 2022
Historique:
pubmed:
14
6
2022
medline:
25
6
2022
entrez:
13
6
2022
Statut:
ppublish
Résumé
The perinucleolar compartment (PNC) is a dynamic subnuclear body found at the periphery of the nucleolus. The PNC is enriched with RNA transcripts and RNA-binding proteins, reflecting different states of genome organization. PNC prevalence positively correlates with cancer progression and metastatic capacity, making it a useful marker for metastatic cancer progression. A high-throughput, high-content assay was developed to identify novel small molecules that selectively reduce PNC prevalence in cancer cells. We identified and further optimized a pyrrolopyrimidine series able to reduce PNC prevalence in PC3M cancer cells at submicromolar concentrations without affecting cell viability. Structure-activity relationship exploration of the structural elements necessary for activity resulted in the discovery of several potent compounds. Analysis of
Identifiants
pubmed: 35696646
doi: 10.1021/acs.jmedchem.2c00204
pmc: PMC10024865
mid: NIHMS1867310
doi:
Substances chimiques
Biomarkers
0
Pyrimidines
0
Pyrroles
0
pyrrolopyrimidine
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
8303-8331Subventions
Organisme : NIMH NIH HHS
ID : R03 MH082371
Pays : United States
Organisme : NHGRI NIH HHS
ID : U54 HG005031
Pays : United States
Références
Mol Cell. 2018 Nov 1;72(3):525-540.e13
pubmed: 30318443
Cold Spring Harb Symp Quant Biol. 2010;75:599-605
pubmed: 21289045
Bioorg Med Chem. 2017 Feb 1;25(3):1266-1276
pubmed: 28082071
Mol Cancer. 2011 Feb 22;10:22
pubmed: 21342498
Nat Rev Clin Oncol. 2019 Mar;16(3):185-204
pubmed: 30514977
Drug Metab Dispos. 2016 Oct;44(10):1653-61
pubmed: 27417180
Immunol Allergy Clin North Am. 2011 Feb;31(1):109-32
pubmed: 21094927
J Cheminform. 2020 Apr 7;12(1):21
pubmed: 33431020
Cancer Res. 2005 Jan 1;65(1):246-53
pubmed: 15665301
Front Biosci (Landmark Ed). 2011 Jan 01;16(3):838-48
pubmed: 21196206
Science. 2011 Mar 25;331(6024):1559-64
pubmed: 21436443
Semin Cancer Biol. 2015 Dec;35 Suppl:S244-S275
pubmed: 25865774
Cancer Chemother Pharmacol. 2020 Apr;85(4):805-816
pubmed: 32185484
J Surg Oncol. 2011 May 1;103(6):508-17
pubmed: 21480243
Crit Rev Oncog. 2015;20(5-6):449-73
pubmed: 27279241
Clin Colorectal Cancer. 2014 Sep;13(3):135-44
pubmed: 24768040
Cancer Chemother Pharmacol. 2018 Dec;82(6):1067-1080
pubmed: 30306263
Bonekey Rep. 2013 Feb 06;2:267
pubmed: 24422040
Sci Transl Med. 2018 May 16;10(441):
pubmed: 29769289
J Cell Biochem. 2009 May 15;107(2):189-93
pubmed: 19288520
Signal Transduct Target Ther. 2019 Aug 9;4:26
pubmed: 31637006
Arch Pharm (Weinheim). 1975 Mar;308(3):179-85
pubmed: 1130955
J Biomol Screen. 2009 Oct;14(9):1045-53
pubmed: 19762548
Signal Transduct Target Ther. 2020 Mar 12;5(1):28
pubmed: 32296047
J Biol Chem. 2009 Feb 13;284(7):4090-101
pubmed: 19015260