Novel non-covalent LSD1 inhibitors endowed with anticancer effects in leukemia and solid tumor cellular models

  • Eur J Med Chem. 2022 Jul 5;237:114410. doi: 10.1016/j.ejmech.2022.114410.
Martina Menna  1 ,  Francesco Fiorentino  1 ,  Biagina Marrocco  2 ,  Alessia Lucidi  1 ,  Stefano Tomassi  3 ,  Domenica Cilli  4 ,  Mauro Romanenghi  4 ,  Matteo Cassandri  5 ,  Silvia Pomella  5 ,  Michele Pezzella  5 ,  Donatella Del Bufalo  6 ,  Mohammad Salik Zeya Ansari  7 ,  Nevena Tomašević  8 ,  Milan Mladenović  8 ,  Monica Viviano  9 ,  Gianluca Sbardella  9 ,  Rossella Rota  5 ,  Daniela Trisciuoglio  10 ,  Saverio Minucci  11 ,  Andrea Mattevi  2 ,  Dante Rotili  12 ,  Antonello Mai  13
Affiliations
  • 1. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy.
  • 2. Department of Biology and Biotechnology, University of Pavia, Via Ferrata 9, 27100, Pavia, Italy.
  • 3. Department of Pharmacy, University of Naples "Federico II", via Domenico Montesano 49, 80131, Naples, Italy.
  • 4. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy.
  • 5. Department of Oncohematology, Bambino Gesù Children's Hospital, IRCCS, viale di San Paolo 15, 00146, Rome, Italy.
  • 6. Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy.
  • 7. Department of Biology and Biotechnology "Charles Darwin", Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.
  • 8. Kragujevac Center for Computational Biochemistry, Department of Chemistry, Faculty of Science, University of Kragujevac, Radoja Domanovića 12, 34000, Kragujevac, P.O. Box 60, Serbia.
  • 9. Department of Pharmacy, University of Salerno, via Giovanni Paolo II, 132, 84084, Fisciano, SA, Italy.
  • 10. Preclinical Models and New Therapeutic Agents Unit, IRCCS-Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy; Institute of Molecular Biology and Pathology, National Research Council (CNR), Via degli Apuli 4, 00185, Rome, Italy.
  • 11. Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, via Adamello 16, 20139, Milan, Italy; Department of Biosciences, University of Milan, Via Festa del Perdono 7, 20122, Milano, Italy.
  • 12. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: [email protected].
  • 13. Department of Drug Chemistry and Technologies, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy; Pasteur Institute, Cenci-Bolognetti Foundation, Sapienza University of Rome, P. le A. Moro 5, 00185, Rome, Italy. Electronic address: [email protected].
PMID: 35525212 DOI: 10.1016/j.ejmech.2022.114410
Abstract

LSD1 is a histone lysine demethylase proposed as therapeutic target in Cancer. Chemical modifications applied at C2, C4 and/or C7 positions of the quinazoline core of the previously reported dual LSD1/G9a inhibitor 1 led to a series of non-covalent, highly active, and selective LSD1 inhibitors (2-4 and 6-30) and to the dual LSD1/G9a inhibitor 5 that was more potent than 1 against LSD1. In THP-1 and MV4-11 leukemic cells, the most potent compounds (7, 8, and 29) showed antiproliferative effects at sub-micromolar level without significant toxicity at 1 μM in non-cancer AHH-1 cells. In MV4-11 cells, the new derivatives increased the levels of the LSD1 histone MARK H3K4me2 and induced the re-expression of the CD86 gene silenced by LSD1, thereby confirming the inhibition of LSD1 at cellular level. In breast MDA-MB-231 as well as in rhabdomyosarcoma RD and RH30 cells, taken as examples of solid tumors, the same compounds displayed cell growth arrest in the same IC50 range, highlighting a crucial Anticancer role for LSD1 inhibition and suggesting no added value for the simultaneous G9a inhibition in these tumor cell lines.

Keywords
Cancer; Drug discovery; Histone lysine methyltransferases; Lysine-specific demethylase 1; Polypharmacology.
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