TY - JOUR
T1 - Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors
T2 - Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model
AU - Depauw, Sabine
AU - Lambert, Mélanie
AU - Jambon, Samy
AU - Paul, Ananya
AU - Peixoto, Paul
AU - Nhili, Raja
AU - Marongiu, Laura
AU - Figeac, Martin
AU - Dassi, Christelle
AU - Paul-Constant, Charles
AU - Billoré, Benjamin
AU - Kumar, Arvind
AU - Farahat, Abdelbasset A.
AU - Ismail, Mohamed A.
AU - Mineva, Ekaterina
AU - Sweat, Daniel P.
AU - Stephens, Chad E.
AU - Boykin, David W.
AU - Wilson, W. David
AU - David-Cordonnier, Marie Hélène
N1 - Publisher Copyright:
Copyright © 2019 American Chemical Society.
PY - 2019/2/14
Y1 - 2019/2/14
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b01448
DO - 10.1021/acs.jmedchem.8b01448
M3 - Article
C2 - 30645099
AN - SCOPUS:85061287743
SN - 0022-2623
VL - 62
SP - 1306
EP - 1329
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 3
ER -