Small-Molecule Activation of Protein Phosphatase 2A Counters Bleomycin-Induced Fibrosis in Mice.
Journal
ACS pharmacology & translational science
ISSN: 2575-9108
Titre abrégé: ACS Pharmacol Transl Sci
Pays: United States
ID NLM: 101721411
Informations de publication
Date de publication:
10 Nov 2023
10 Nov 2023
Historique:
received:
12
06
2023
pmc-release:
17
10
2024
medline:
17
11
2023
pubmed:
17
11
2023
entrez:
17
11
2023
Statut:
epublish
Résumé
The activity of protein phosphatase 2A (PP2A), a serine-threonine phosphatase, is reduced in the lung fibroblasts of idiopathic pulmonary fibrosis (IPF) patients. The objective of this study was to determine whether the reactivation of PP2A could reduce fibrosis and preserve the pulmonary function in a bleomycin (BLM) mouse model. Here, we present a new class of direct small-molecule PP2A activators, diarylmethyl-pyran-sulfonamide, exemplified by ATUX-1215. ATUX-1215 has improved metabolic stability and bioavailability compared to our previously described PP2A activators. Primary human lung fibroblasts were exposed to ATUX-1215 and an older generation PP2A activator in combination with TGFβ. ATUX-1215 treatment enhanced the PP2A activity, reduced the phosphorylation of ERK and JNK, and reduced the TGFβ-induced expression of
Identifiants
pubmed: 37974628
doi: 10.1021/acsptsci.3c00117
pmc: PMC10644462
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1659-1672Informations de copyright
© 2023 American Chemical Society.
Déclaration de conflit d'intérêts
The authors declare the following competing financial interest(s): MO is owner of Atux Iskay LLC. Other authors have no competing interests.
Références
Science. 2021 Nov 12;374(6569):883-887
pubmed: 34762484
Am J Respir Cell Mol Biol. 2018 Dec;59(6):695-705
pubmed: 30011381
Crit Care Med. 1995 Aug;23(8):1405-11
pubmed: 7634812
Brain Commun. 2020 Jan 11;2(1):fcaa002
pubmed: 32954276
J Immunol. 2017 Jun 1;198(11):4470-4480
pubmed: 28455433
Environ Mol Mutagen. 1997;30(1):11-20
pubmed: 9258325
Am J Respir Crit Care Med. 2010 Feb 15;181(4):394-418
pubmed: 20130146
Mol Cell. 2020 Oct 15;80(2):345-358.e9
pubmed: 32966759
Toxicol Sci. 2012 Apr;126(2):589-99
pubmed: 22223484
Acta Pharm Sin B. 2022 Jan;12(1):18-32
pubmed: 35127370
Immunity. 2016 Mar 15;44(3):582-596
pubmed: 26921108
Clin Cancer Res. 2017 Jul 1;23(13):3277-3284
pubmed: 28039265
Science. 2020 Nov 27;370(6520):
pubmed: 33243860
Mol Biol Cell. 2010 Mar 15;21(6):1140-52
pubmed: 20110348
J Pediatr Surg. 2023 Jun;58(6):1145-1154
pubmed: 36907775
Am J Respir Cell Mol Biol. 2015 Sep;53(3):391-9
pubmed: 25612003
Respir Med. 2002 Feb;96(2):67-80
pubmed: 11862964
Respir Res. 2019 Oct 17;20(1):222
pubmed: 31623614
Eur Respir J. 2011 Nov;38(5):1019-28
pubmed: 21622588
EMBO J. 2022 Jul 18;41(14):e110611
pubmed: 35695070
Medicina (Kaunas). 2018 Dec 10;54(6):
pubmed: 30544758
J Vis Exp. 2013 May 15;(75):e50080
pubmed: 23711820
J Pharmacol Exp Ther. 2014 Nov;351(2):352-8
pubmed: 25187431
Proc Natl Acad Sci U S A. 2010 Feb 9;107(6):2467-72
pubmed: 20133745
Am J Pathol. 2012 Jul;181(1):222-33
pubmed: 22642910
Philos Trans R Soc Lond B Biol Sci. 2018 Jun 19;373(1749):
pubmed: 29735741
EMBO Mol Med. 2018 Feb;10(2):276-293
pubmed: 29217661
Cancers (Basel). 2022 Apr 13;14(8):
pubmed: 35454859
Toxicol Appl Pharmacol. 2022 Nov 1;454:116228
pubmed: 36087614
PLoS One. 2014 Feb 28;9(2):e90567
pubmed: 24587397
Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L864-70
pubmed: 19700647
Trends Biochem Sci. 1999 May;24(5):186-91
pubmed: 10322434
Int J Biochem Cell Biol. 2018 Mar;96:157-164
pubmed: 29355757
Nat Commun. 2023 Feb 28;14(1):1143
pubmed: 36854761
Am J Respir Crit Care Med. 2019 Jul 1;200(1):51-62
pubmed: 30641028
Bioorg Med Chem. 2015 Oct 1;23(19):6528-34
pubmed: 26372073
Proc Am Thorac Soc. 2005;2(3):214-20
pubmed: 16222040
Clin Microbiol Rev. 2011 Jan;24(1):210-29
pubmed: 21233513
Nat Commun. 2023 Aug 29;14(1):5253
pubmed: 37644036
Cell. 2020 Apr 30;181(3):688-701.e16
pubmed: 32315618
PLoS One. 2011;6(12):e27627
pubmed: 22205926
Exp Lung Res. 2020 Sep;46(7):234-242
pubmed: 32584210
J Med Chem. 2023 Jul 27;66(14):9278-9296
pubmed: 37437222
Am J Respir Crit Care Med. 2022 May 1;205(9):e18-e47
pubmed: 35486072
ERJ Open Res. 2022 Mar 14;8(1):
pubmed: 35295232
Cell. 2009 Oct 30;139(3):468-84
pubmed: 19879837
Mucosal Immunol. 2014 May;7(3):684-93
pubmed: 24172847
Respir Res. 2010 Jun 21;11:82
pubmed: 20565957
Cytokine. 2015 Jul;74(1):88-100
pubmed: 25543535
Nucleic Acids Res. 2019 Jan 8;47(D1):D607-D613
pubmed: 30476243
J Clin Invest. 1996 Feb 15;97(4):1102-10
pubmed: 8613534
BMC Pulm Med. 2019 Feb 7;19(1):31
pubmed: 30732588
Am J Respir Crit Care Med. 2018 Sep 1;198(5):e44-e68
pubmed: 30168753
Am J Respir Cell Mol Biol. 2012 Mar;46(3):380-8
pubmed: 22021337
Am J Respir Crit Care Med. 2014 Dec 1;190(11):1229-42
pubmed: 25341065
Pharmacol Ther. 2019 Sep;201:181-201
pubmed: 31158394
Sci Transl Med. 2021 Apr 7;13(588):
pubmed: 33827975
Cell. 2021 Jun 10;184(12):3143-3162.e32
pubmed: 34004147
J Immunol. 2000 Oct 1;165(7):4032-9
pubmed: 11034414
Int J Mol Sci. 2021 Jun 03;22(11):
pubmed: 34204949
J Clin Invest. 2017 Jun 1;127(6):2081-2090
pubmed: 28504649
EMBO Mol Med. 2013 Jan;5(1):105-21
pubmed: 23180565
Biochim Biophys Acta Mol Cell Res. 2019 Jan;1866(1):31-50
pubmed: 30030003