Quinazoline-Based Analog of Adenine As an Antidote Against MLL-rearranged Leukemia Cells: Synthesis, Inhibition Assays and Docking Studies

Abstract

Background: Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.

Keywords: :

• adenine analogs
• bisubstrate inhibitors
• chemical probes
• DOT1L
• epigenetics
• MLLr leukemia

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at:www.tandfonline.com/doi/full/10.2217/epi-2016-0184

Acknowledgments

The authors thank B Vitorge from the Institut Pasteur Biological NMR Technological Platform for helping with NMR experiments and F Bonhomme and S Vichier-Guerre of the Centre National de la Recherche Scientifique–Institut Pasteur UMR3523 Organic Chemistry Unit for assisting with high-resolution mass spectrometry analysis. The authors also thank the Image Analysis Hub at Institut Pasteur (J-Y Tinevez, S Rigaud, D Ershov, MS Phan) for help with analysis of images acquired by confocal microscope.

Financial & competing interests disclosure

This research was supported by a Région Ile de France PhD fellowship to C Bon (ARDoC); DIM OneHealth Investissements to PB Arimondo; Le Comité de Paris de la Ligue Contre la Cancer (Epi-Med 2020–2021) to PB Arimondo; and Hubert Curien Partnership Project for collaboration France–Serbia 2020–2022 (Pavle Savić 2020) to PB Arimondo and K Nikolic. The authors collaborated in the frame of the EU COST CM1406 Epigenetic Chemical Biology program. D Ruzic, N Djokovic and K Nikolic acknowledge a Ministry of Education, Science and Technological Development of the Republic of Serbia Faculty of Pharmacy project (451-03-9/2021-14/200161). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.