CN470 is a BET/CBP/p300 multi-bromodomain inhibitor and has an anti-tumor activity against MLL-rearranged acute lymphoblastic leukemia.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Cell Cycle Checkpoints
/ drug effects
Cell Line, Tumor
Cell Proliferation
/ drug effects
E1A-Associated p300 Protein
/ antagonists & inhibitors
Gene Expression Regulation, Leukemic
/ drug effects
Gene Rearrangement
/ drug effects
Histone-Lysine N-Methyltransferase
/ genetics
Humans
Mice
Myeloid-Lymphoid Leukemia Protein
/ genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ genetics
RNA, Messenger
/ genetics
Survival Analysis
Xenograft Model Antitumor Assays
ALL
BET
Bromodomain
CBP/p300
MLL
PDX
Journal
Biochemical and biophysical research communications
ISSN: 1090-2104
Titre abrégé: Biochem Biophys Res Commun
Pays: United States
ID NLM: 0372516
Informations de publication
Date de publication:
29 01 2022
29 01 2022
Historique:
received:
20
12
2021
accepted:
21
12
2021
pubmed:
1
1
2022
medline:
11
2
2022
entrez:
31
12
2021
Statut:
ppublish
Résumé
Acute lymphoblastic leukemia with chromosomal rearrangements involving the mixed-lineage leukemia (MLL) gene (MLL-r ALL) remains an incurable disease. Thus, development of a safe and effective therapeutic agent to treat this disease is crucial to address this unmet medical need. BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, and cyclic AMP response element binding protein binding protein (CBP) and p300, two paralogous histone acetyltransferases, are all considered cancer drug targets and simultaneous targeting of these proteins may have therapeutic advantages. Here, we demonstrate that a BET/CBP/p300 multi-bromodomain inhibitor, CN470, has anti-tumor activity against MLL-r ALL in vitro and in vivo. CN470, potently inhibited ligand binding to the bromodomains of BRD4, CBP, and p300 and suppressed the growth of MLL-r ALL cell lines and patient-derived cells with MLL rearrangements. CN470 suppressed mRNA and protein expression of MYC and induced apoptosis in MLL-r ALL cells, following a cell cycle arrest in the G1 phase. Moreover, CN470 reduced BRD4 binding to acetylated histone H3. The in vivo effects of CN470 were investigated using SEM
Identifiants
pubmed: 34971957
pii: S0006-291X(21)01719-8
doi: 10.1016/j.bbrc.2021.12.078
pmc: PMC8898544
mid: NIHMS1778868
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
KMT2A protein, human
0
RNA, Messenger
0
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
E1A-Associated p300 Protein
EC 2.3.1.48
EP300 protein, human
EC 2.3.1.48
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
49-54Subventions
Organisme : Intramural NIH HHS
ID : Z99 TR999999
Pays : United States
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.
Déclaration de conflit d'intérêts
Declaration of competing interest N. Imayoshi, K. Tanaka, S.-M. Yang, K. Akahane, Y. Toda, S. Hosogi, T. Inukai, S, Okada, D. J. Maloney, I. Kato and E. Ashihara have no financial conflict of interest to disclose. M. Yoshioka is an employee of ConverGene LLC and holds equity in the company.
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