2. Academic Validation
  3. Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model

Heterocyclic Diamidine DNA Ligands as HOXA9 Transcription Factor Inhibitors: Design, Molecular Evaluation, and Cellular Consequences in a HOXA9-Dependant Leukemia Cell Model

  • J Med Chem. 2019 Feb 14;62(3):1306-1329. doi: 10.1021/acs.jmedchem.8b01448.
Sabine Depauw 1,  Mélanie Lambert 1,  Samy Jambon 1,  Ananya Paul 2,  Paul Peixoto 1,  Raja Nhili 1,  Laura Marongiu 1,  Martin Figeac 3,  Christelle Dassi 1,  Charles Paul-Constant 1,  Benjamin Billoré 1,  Arvind Kumar 2,  Abdelbasset A Farahat 2,  Mohamed A Ismail 2,  Ekaterina Mineva 2,  Daniel P Sweat 4,  Chad E Stephens 4,  David W Boykin 2,  W David Wilson 2,  Marie-Hélène David-Cordonnier 1
Affiliations

Affiliations

  • 1 UMR-S1172-JPARC (Jean-Pierre Aubert Research Center), INSERM, University of Lille, Centre Hospitalier Universitaire de Lille, Institut pour la Recherche sur le Cancer de Lille (IRCL) , F-59045 Lille , France.
  • 2 Department of Chemistry , Georgia State University , Atlanta , Georgia 30303 , United States.
  • 3 Functional and Structural Genomic Platform , Lille University , F-59000 Lille , France.
  • 4 Department of Chemistry and Physics , Augusta University , Augusta , Georgia 30904 , United States.
PMID: 30645099 DOI: 10.1021/acs.jmedchem.8b01448
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.

Figures