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Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2019 Feb 14; Vol. 62 (3), pp. 1306-1329. Date of Electronic Publication: 2019 Feb 01. - Publication Year :
- 2019
-
Abstract
- Most transcription factors were for a long time considered as undruggable targets because of the absence of binding pockets for direct targeting. HOXA9, implicated in acute myeloid leukemia, is one of them. To date, only indirect targeting of HOXA9 expression or multitarget HOX/PBX protein/protein interaction inhibitors has been developed. As an attractive alternative by inhibiting the DNA binding, we selected a series of heterocyclic diamidines as efficient competitors for the HOXA9/DNA interaction through binding as minor groove DNA ligands on the HOXA9 cognate sequence. Selected DB818 and DB1055 compounds altered HOXA9-mediated transcription in luciferase assays, cell survival, and cell cycle, but increased cell death and granulocyte/monocyte differentiation, two main HOXA9 functions also highlighted using transcriptomic analysis of DB818-treated murine Hoxa9-transformed hematopoietic cells. Altogether, these data demonstrate for the first time the propensity of sequence-selective DNA ligands to inhibit HOXA9/DNA binding both in vitro and in a murine Hoxa9-dependent leukemic cell model.
- Subjects :
- Cell Death drug effects
Cell Proliferation drug effects
DNA chemistry
Drug Design
Gene Expression drug effects
Heterocyclic Compounds chemistry
Leukemia genetics
Ligands
DNA drug effects
Heterocyclic Compounds pharmacology
Homeodomain Proteins antagonists & inhibitors
Leukemia pathology
Models, Biological
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 62
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30645099
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.8b01448