2. Academic Validation
  3. Development of Small Molecule MEIS Inhibitors that modulate HSC activity

Development of Small Molecule MEIS Inhibitors that modulate HSC activity

  • Sci Rep. 2020 May 14;10(1):7994. doi: 10.1038/s41598-020-64888-3.
Raife Dilek Turan 1 2,  Esra Albayrak 1,  Merve Uslu 1,  Pinar Siyah 1,  Lamia Yazgi Alyazici 1,  Batuhan Mert Kalkan 3,  Galip Servet Aslan 4,  Dogacan Yucel 5,  Merve Aksoz 6,  Emre Can Tuysuz 7,  Neslihan Meric 1 8,  Serdar Durdagi 9,  Zafer Gulbas 8,  Fatih Kocabas 10
Affiliations

Affiliations

  • 1 Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey.
  • 2 LabCell, Acibadem University, Istanbul, Turkey.
  • 3 Koc University, Istanbul, Turkey.
  • 4 Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany.
  • 5 Faculty of Medicine, University of Minnesota, Minnesota, USA.
  • 6 MRC Molecular Hematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK.
  • 7 Department of Medical Genetics, Faculty of Medicine, Yeditepe University, Istanbul, Turkey.
  • 8 Bone Marrow Transplantation Center, Anadolu Medical Center, Kocaeli, Turkey.
  • 9 Department of Biophysics, School of Medicine, Bahcesehir University, Istanbul, Turkey.
  • 10 Regenerative Biology Research Laboratory, Department of Genetics and Bioengineering, Faculty of Engineering, Yeditepe University, Istanbul, Turkey. Fatih.Kocabas@yeditepe.edu.tr.
PMID: 32409701 DOI: 10.1038/s41598-020-64888-3
Abstract

Meis1, which belongs to TALE-type class of homeobox gene family, appeared as one of the key regulators of hematopoietic stem cell (HSC) self-renewal and a potential therapeutical target. However, small molecule inhibitors of MEIS1 remained unknown. This led us to develop inhibitors of MEIS1 that could modulate HSC activity. To this end, we have established a library of relevant homeobox family inhibitors and developed a high-throughput in silico screening strategy against homeodomain of MEIS proteins using the AutoDock Vina and PaDEL-ADV platform. We have screened over a million druggable small molecules in silico and selected putative MEIS inhibitors (MEISi) with no predicted cytotoxicity or cardiotoxicity. This was followed by in vitro validation of putative MEIS inhibitors using MEIS dependent luciferase reporter assays and analysis in the ex vivo HSC assays. We have shown that small molecules named MEISi-1 and MEISi-2 significantly inhibit MEIS-luciferase reporters in vitro and induce murine (LSKCD34l°w cells) and human (CD34+, CD133+, and ALDHhi cells) HSC self-renewal ex vivo. In addition, inhibition of MEIS proteins results in downregulation of Meis1 and MEIS1 target gene expression including HIF-1α, Hif-2α and HSC quiescence modulators. MEIS inhibitors are effective in vivo as evident by induced HSC content in the murine bone marrow and downregulation of expression of MEIS target genes. These studies warrant identification of first-in-class MEIS inhibitors as potential pharmaceuticals to be utilized in modulation of HSC activity and bone marrow transplantation studies.

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