A cell competition-based small molecule screen identifies a novel compound that induces dual c-Myc depletion and p53 activation.
Abl
anticancer drug
c-Myc
drug screening
leukemia
mRNA
p53
phosphoproteomics
tyrosine kinase
Journal
The Journal of biological chemistry
ISSN: 1083-351X
Titre abrégé: J Biol Chem
Pays: United States
ID NLM: 2985121R
Informations de publication
Date de publication:
Historique:
received:
18
07
2020
revised:
26
11
2020
accepted:
10
12
2020
pubmed:
12
12
2020
medline:
31
8
2021
entrez:
11
12
2020
Statut:
ppublish
Résumé
Breakpoint Cluster Region-Abelson kinase (BCR-Abl) is a driver oncogene that causes chronic myeloid leukemia and a subset of acute lymphoid leukemias. Although tyrosine kinase inhibitors provide an effective treatment for these diseases, they generally do not kill leukemic stem cells (LSCs), the cancer-initiating cells that compete with normal hematopoietic stem cells for the bone marrow niche. New strategies to target cancers driven by BCR-Abl are therefore urgently needed. We performed a small molecule screen based on competition between isogenic untransformed cells and BCR-Abl-transformed cells and identified several compounds that selectively impair the fitness of BCR-Abl-transformed cells. Interestingly, systems-level analysis of one of these novel compounds, DJ34, revealed that it induced depletion of c-Myc and activation of p53. DJ34-mediated c-Myc depletion occurred in a wide range of tumor cell types, including lymphoma, lung, glioblastoma, breast cancer, and several forms of leukemia, with primary LSCs being particularly sensitive to DJ34. Further analyses revealed that DJ34 interferes with c-Myc synthesis at the level of transcription, and we provide data showing that DJ34 is a DNA intercalator and topoisomerase II inhibitor. Physiologically, DJ34 induced apoptosis, cell cycle arrest, and cell differentiation. Taken together, we have identified a novel compound that dually targets c-Myc and p53 in a wide variety of cancers, and with particularly strong activity against LSCs.
Identifiants
pubmed: 33303632
pii: S0021-9258(20)00175-1
doi: 10.1074/jbc.RA120.015285
pmc: PMC7948465
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
MYC protein, human
0
Proto-Oncogene Proteins c-myc
0
Small Molecule Libraries
0
Tumor Suppressor Protein p53
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
100179Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest J. M. E. has received research funding from ARIAD pharmaceuticals (now part of Takeda Oncology). The other authors do not declare conflict of interest.
Références
Cancer Res. 2007 Jun 15;67(12):5611-6
pubmed: 17575125
Leuk Res. 1993 Dec;17(12):1045-50
pubmed: 8246608
Cell. 2004 Jul 23;118(2):217-28
pubmed: 15260991
J Clin Invest. 2011 Jan;121(1):396-409
pubmed: 21157039
Adv Cancer Res. 1991;56:1-48
pubmed: 2028839
Genes (Basel). 2017 May 25;8(6):
pubmed: 28587062
Genome Biol. 2003;4(10):R69
pubmed: 14519204
Cold Spring Harb Perspect Med. 2014 Jun 02;4(6):
pubmed: 24890832
Nat Cell Biol. 2002 Nov;4(11):901-6
pubmed: 12402047
Cell. 1992 Sep 18;70(6):901-10
pubmed: 1525828
Mol Cell. 2008 Jun 6;30(5):547-56
pubmed: 18538653
Cancer Cell. 2018 Nov 12;34(5):807-822.e7
pubmed: 30423298
J Med Chem. 1991 Jul;34(7):2023-30
pubmed: 1676758
Blood. 2007 Jun 15;109(12):5411-21
pubmed: 17347407
Blood. 2014 Feb 6;123(6):843-50
pubmed: 24277073
Genome Res. 2015 Jun;25(6):897-906
pubmed: 25800674
Semin Cancer Biol. 2016 Feb;36:33-51
pubmed: 26432751
J Biol Chem. 2011 Nov 25;286(47):41018-27
pubmed: 21956115
Cell Stem Cell. 2015 Mar 5;16(3):254-67
pubmed: 25748932
Nat Chem Biol. 2012 Jan 29;8(3):285-93
pubmed: 22286129
Nat Rev Clin Oncol. 2015 Jun;12(6):344-57
pubmed: 25781572
Cancer Discov. 2014 Feb;4(2):200-15
pubmed: 24362263
Nature. 2016 Jun 08;534(7607):341-6
pubmed: 27281222
Mol Cell Biol. 2001 Dec;21(24):8437-51
pubmed: 11713279
Nat Rev Drug Discov. 2011 Jun 24;10(7):507-19
pubmed: 21701501
Nat Commun. 2015 Feb 13;6:6265
pubmed: 25677187
Genes Dev. 1998 Aug 1;12(15):2263-8
pubmed: 9694792
Cold Spring Harb Symp Quant Biol. 2008;73:427-37
pubmed: 19150964
Biochem Pharmacol. 1994 Jan 20;47(2):317-29
pubmed: 8304976
Cancer Res. 2001 Jun 15;61(12):4910-5
pubmed: 11406570
Nat Med. 1997 Jul;3(7):730-7
pubmed: 9212098
Nature. 2009 Apr 9;458(7239):732-6
pubmed: 19360080
Clin Cancer Res. 2012 Feb 15;18(4):930-7
pubmed: 22156549
Sci Rep. 2017 Mar 03;7:42717
pubmed: 28256516
Proc Natl Acad Sci U S A. 1986 Oct;83(20):7918-22
pubmed: 3464006
Mol Cell. 2002 May;9(5):1031-44
pubmed: 12049739
Blood. 2008 Dec 15;112(13):4793-807
pubmed: 19064739
Cancers (Basel). 2014 Feb 26;6(1):436-58
pubmed: 24577242
Nucleic Acids Res. 2018 Dec 14;46(22):11698-11711
pubmed: 30247619
Nat Rev Drug Discov. 2017 Aug;16(8):531-543
pubmed: 28685762
Mol Cell Proteomics. 2014 May;13(5):1392-6
pubmed: 24591702
Proc Natl Acad Sci U S A. 2003 Jul 8;100(14):8164-9
pubmed: 12808131
Cancer Res. 2007 Oct 1;67(19):9006-12
pubmed: 17909001
Mol Divers. 2010 May;14(2):401-8
pubmed: 19685275
Science. 2013 Jun 21;340(6139):1412-3
pubmed: 23788787
Cell. 2013 Jun 20;153(7):1552-66
pubmed: 23791182
Hum Mutat. 2016 Sep;37(9):865-76
pubmed: 27328919
Cold Spring Harb Perspect Med. 2014 Mar 01;4(3):
pubmed: 24591536
PLoS One. 2014 Aug 15;9(8):e105381
pubmed: 25127121
J Biol Chem. 2015 Jul 10;290(28):17495-504
pubmed: 26023239
Blood. 2008 Feb 15;111(4):2170-80
pubmed: 17925489
Oncogene. 2013 Apr 25;32(17):2239-46
pubmed: 22710719
Science. 2001 Oct 5;294(5540):173-7
pubmed: 11533444
Nucleic Acids Res. 2018 Jun 20;46(11):5355-5365
pubmed: 29762718
Blood. 2000 Mar 15;95(6):2104-10
pubmed: 10706881
J Biol Chem. 2008 Jan 25;283(4):1882-92
pubmed: 18042541
PLoS One. 2013 Sep 02;8(9):e72846
pubmed: 24023784