2. Academic Validation
  3. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

  • J Med Chem. 2022 Apr 14;65(7):5701-5723. doi: 10.1021/acs.jmedchem.1c02228.
Prashant Khirsariya 1 2,  Patrik Pospíšil 1,  Lukáš Maier 1 2,  Miroslav Boudný 3 4,  Martin Babáš 3,  Ondřej Kroutil 3,  Marek Mráz 3 4,  Robert Vácha 3,  Kamil Paruch 1 2
Affiliations

Affiliations

  • 1 Department of Chemistry, CZ Openscreen, Faculty of Science, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
  • 2 International Clinical Research Center, Center for Biomolecular and Cellular Engineering, St. Anne's University Hospital in Brno, 602 00 Brno, Czech Republic.
  • 3 Central European Institute of Technology, Masaryk University, Kamenice 5, 625 00 Brno, Czech Republic.
  • 4 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno and Faculty of Medicine, Masaryk University, Jihlavska 20, 625 00 Brno, Czech Republic.
PMID: 35302777 DOI: 10.1021/acs.jmedchem.1c02228
Abstract

Histone Methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (-)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.

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