Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors

Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model

Sabine Depauw, Mélanie Lambert, Samy Jambon, Ananya Paul, Paul Peixoto, Raja Nhili, Laura Marongiu, Martin Figeac, Christelle Dassi, Charles Paul-Constant, Benjamin Billoré, Arvind Kumar, Abdelbasset A. Farahat, Mohamed A. Ismail, Ekaterina Mineva, Daniel P. Sweat, Chad E. Stephens, David W. Boykin, W. David Wilson, Marie Hélène David-Cordonnier

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1306-1329
Number of pages24
JournalJournal of Medicinal Chemistry
Volume62
Issue number3
DOIs
StatePublished - Feb 14 2019

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Pentamidine
Leukemia
Transcription Factors
Ligands
DNA
Luciferases
Granulocytes
Acute Myeloid Leukemia
Monocytes
Cell Survival
Cell Cycle
Proteins
Cell Death

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors : Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model. / Depauw, Sabine; Lambert, Mélanie; Jambon, Samy; Paul, Ananya; Peixoto, Paul; Nhili, Raja; Marongiu, Laura; Figeac, Martin; Dassi, Christelle; Paul-Constant, Charles; Billoré, Benjamin; Kumar, Arvind; Farahat, Abdelbasset A.; Ismail, Mohamed A.; Mineva, Ekaterina; Sweat, Daniel P.; Stephens, Chad E.; Boykin, David W.; Wilson, W. David; David-Cordonnier, Marie Hélène.

In: Journal of Medicinal Chemistry, Vol. 62, No. 3, 14.02.2019, p. 1306-1329.

Research output: Contribution to journalArticle

Depauw, S, Lambert, M, Jambon, S, Paul, A, Peixoto, P, Nhili, R, Marongiu, L, Figeac, M, Dassi, C, Paul-Constant, C, Billoré, B, Kumar, A, Farahat, AA, Ismail, MA, Mineva, E, Sweat, DP, Stephens, CE, Boykin, DW, Wilson, WD & David-Cordonnier, MH 2019, 'Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model', Journal of Medicinal Chemistry, vol. 62, no. 3, pp. 1306-1329. https://doi.org/10.1021/acs.jmedchem.8b01448
Depauw, Sabine ; Lambert, Mélanie ; Jambon, Samy ; Paul, Ananya ; Peixoto, Paul ; Nhili, Raja ; Marongiu, Laura ; Figeac, Martin ; Dassi, Christelle ; Paul-Constant, Charles ; Billoré, Benjamin ; Kumar, Arvind ; Farahat, Abdelbasset A. ; Ismail, Mohamed A. ; Mineva, Ekaterina ; Sweat, Daniel P. ; Stephens, Chad E. ; Boykin, David W. ; Wilson, W. David ; David-Cordonnier, Marie Hélène. / Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors : Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 3. pp. 1306-1329.
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AU - Lambert, Mélanie

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AU - Paul, Ananya

AU - Peixoto, Paul

AU - Nhili, Raja

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AU - Dassi, Christelle

AU - Paul-Constant, Charles

AU - Billoré, Benjamin

AU - Kumar, Arvind

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AU - Sweat, Daniel P.

AU - Stephens, Chad E.

AU - Boykin, David W.

AU - Wilson, W. David

AU - David-Cordonnier, Marie Hélène

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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.

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