Antitumor activity of the dual BET and CBP/EP300 inhibitor NEO2734.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
08 09 2020
08 09 2020
Historique:
received:
16
03
2020
accepted:
27
07
2020
entrez:
4
9
2020
pubmed:
4
9
2020
medline:
15
5
2021
Statut:
ppublish
Résumé
Bromodomain and extra-terminal domain (BET) proteins, cyclic adenosine monophosphate response element-binding protein (CBP), and the E1A-binding protein of p300 (EP300) are important players in histone acetylation. Preclinical evidence supports the notion that small molecules targeting these proteins individually or in combination can elicit antitumor activity. Here, we characterize the antitumor activity of the pan BET/CBP/EP300 inhibitor NEO2734 and provide insights into its mechanism of action through bromodomain-binding assays, in vitro and in vivo treatments of cancer cell lines, immunoblotting, and transcriptome analyses. In a panel of 60 models derived from different tumor types, NEO2734 exhibited antiproliferative activity in multiple cell lines, with the most potent activity observed in hematologic and prostate cancers. Focusing on lymphoma cell lines, NEO2374 exhibited a pattern of response and transcriptional changes similar to lymphoma cells exposed to either BET or CBP/EP300 inhibitors alone. However, NEO2734 was more potent than single-agent BET or CBP/EP300 inhibitors alone. In conclusion, NEO2734 is a novel antitumor compound that shows preferential activity in lymphomas, leukemias, and prostate cancers.
Identifiants
pubmed: 32882003
pii: S2473-9529(20)31175-7
doi: 10.1182/bloodadvances.2020001879
pmc: PMC7479962
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4124-4135Informations de copyright
© 2020 by The American Society of Hematology.
Références
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Nature. 2004 May 27;429(6990):457-63
pubmed: 15164071
Pharmacol Ther. 2020 Nov;215:107631
pubmed: 32693114
Clin Cancer Res. 2017 Feb 15;23(4):1025-1035
pubmed: 28073847
Oncotarget. 2016 Nov 29;7(48):79637-79653
pubmed: 27793034
N Engl J Med. 2012 Aug 16;367(7):647-57
pubmed: 22894577
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Lancet Haematol. 2016 Apr;3(4):e186-95
pubmed: 27063977
Haematologica. 2019 Dec;104(12):e558-e561
pubmed: 31018978
Nat Protoc. 2016 Jan;11(1):1-9
pubmed: 26633127
Clin Cancer Res. 2018 Jan 1;24(1):120-129
pubmed: 29066507
Proc Natl Acad Sci U S A. 2014 Aug 5;111(31):11365-70
pubmed: 25049379
Haematologica. 2020 Aug;105(8):e432-e436
pubmed: 32467139
Mol Cancer Ther. 2016 Sep;15(9):2030-41
pubmed: 27406984
Elife. 2016 Jan 05;5:
pubmed: 26731516
Clin Cancer Res. 2019 Aug 15;25(16):5167-5176
pubmed: 31182435
Cancer Discov. 2013 Mar;3(3):308-23
pubmed: 23430699
Mol Cell. 1998 Apr;1(5):661-71
pubmed: 9660950
Nature. 2011 Jul 27;476(7360):298-303
pubmed: 21796119
Cancer Discov. 2018 Jan;8(1):24-36
pubmed: 29263030
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Oncotarget. 2015 Mar 10;6(7):5059-71
pubmed: 25671298
Cancer Discov. 2016 Apr;6(4):430-45
pubmed: 26603525
J Clin Oncol. 2018 Oct 20;36(30):3007-3014
pubmed: 29733771
EMBO Mol Med. 2019 Nov 7;11(11):e10659
pubmed: 31559706
Immunity. 2019 Sep 17;51(3):535-547.e9
pubmed: 31519498
J Med Chem. 2011 Oct 13;54(19):6761-70
pubmed: 21851057
Explor Target Antitumor Ther. 2021;2(6):586-601
pubmed: 36046113
J Med Chem. 2014 Jan 23;57(2):462-76
pubmed: 24313754
Cancer Cell. 2013 Dec 9;24(6):777-90
pubmed: 24332044
Cancer Res. 2015 Dec 1;75(23):5106-5119
pubmed: 26552700
Clin Cancer Res. 2015 Jan 1;21(1):113-22
pubmed: 25009295
Clin Cancer Res. 2019 Nov 1;25(21):6309-6319
pubmed: 31420359
Mol Cancer Ther. 2020 Jul;19(7):1406-1414
pubmed: 32371576
Haematologica. 2019 Aug;104(8):1633-1639
pubmed: 30733273
Ann Oncol. 2020 Jun;31(6):780-788
pubmed: 32240793
Br J Haematol. 2017 Sep;178(6):936-948
pubmed: 28653353
J Med Chem. 2016 Dec 8;59(23):10549-10563
pubmed: 27682507
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Clin Cancer Res. 2015 Apr 1;21(7):1628-38
pubmed: 25623213
Nature. 2011 Mar 10;471(7337):189-95
pubmed: 21390126
Trends Pharmacol Sci. 2012 Mar;33(3):146-53
pubmed: 22277300
Haematologica. 2020 Jan 09;105(11):2584-2591
pubmed: 33131247
Nature. 2017 Oct 5;550(7674):128-132
pubmed: 28953875
Nat Rev Drug Discov. 2019 Aug;18(8):609-628
pubmed: 31273347
Eur J Haematol. 2021 Jan;106(1):90-99
pubmed: 32997383
Ann Oncol. 2016 Jun;27(6):1123-1128
pubmed: 26961147
Haematologica. 2019 Jun;104(6):e256-e259
pubmed: 30545928
Medchemcomm. 2013 Jan 1;4(1):140-144
pubmed: 26682033
Lancet Haematol. 2016 Apr;3(4):e196-204
pubmed: 27063978
Nat Med. 2017 Sep;23(9):1046-1054
pubmed: 28805821
JNCI Cancer Spectr. 2019 Nov 06;4(2):pkz093
pubmed: 32328561
Mol Cancer Res. 2019 Mar;17(3):720-730
pubmed: 30606771
Hemasphere. 2021 Jul 08;5(8):e610
pubmed: 34258514
Proc Natl Acad Sci U S A. 2015 Aug 25;112(34):10768-73
pubmed: 26261308