Tranylcypromine-Based LSD1 Inhibitors: Structure-Activity Relationships, Antiproliferative Effects in Leukemia, and Gene Target Modulation.
Antineoplastic Agents
/ chemical synthesis
Cell Line, Tumor
Cell Proliferation
/ drug effects
Dose-Response Relationship, Drug
Enzyme Inhibitors
/ chemical synthesis
Histone Demethylases
/ antagonists & inhibitors
Humans
Microsomes, Liver
/ chemistry
Structure-Activity Relationship
Tranylcypromine
/ chemical synthesis
antiproliferative activity
drug discovery
histone demethylases
lysine specific demethylase 1
structure-activity relationships
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
03 04 2020
03 04 2020
Historique:
received:
25
12
2019
pubmed:
1
2
2020
medline:
10
4
2021
entrez:
1
2
2020
Statut:
ppublish
Résumé
LSD1 is a lysine demethylase highly involved in initiation and development of cancer. To design highly effective covalent inhibitors, a strategy is to fill its large catalytic cleft by designing tranylcypromine (TCP) analogs decorated with long, hindered substituents. We prepared three series of TCP analogs, carrying aroyl- and arylacetylamino (1 a-h), Z-amino acylamino (2 a-o), or double-substituted benzamide (3 a-n) residues at the C4 or C3 position of the phenyl ring. Further fragments obtained by chemical manipulation applied on the TCP scaffold (compounds 4 a-i) were also prepared. When tested against LSD1, most of 1 and 3 exhibited IC
Identifiants
pubmed: 32003940
doi: 10.1002/cmdc.201900730
pmc: PMC7125024
mid: NIHMS1558148
doi:
Substances chimiques
Antineoplastic Agents
0
Enzyme Inhibitors
0
Tranylcypromine
3E3V44J4Z9
Histone Demethylases
EC 1.14.11.-
KDM1A protein, human
EC 1.5.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
643-658Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM114306
Pays : United States
Informations de copyright
© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
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